Neoadjuvant Chemoradiotherapy and Immunotherapy Combined With Ketogenic Diet and/or High-Dose Intravenous Vitamin C in pMMR/MSS Locally Advanced Rectal Adenocarcinoma: A Prospective, Multicenter, Phase Ⅱ Clinical Study (CRI-KEV Trial)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- pCR rate
研究概览
简要总结
To explore the efficacy and safety of adding a ketogenic diet and/or high-dose intravenous vitamin C to neoadjuvant short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with serplulimab in patients with locally advanced pMMR/MSS rectal adenocarcinoma through a prospective, randomized, controlled phase II clinical study, providing preliminary evidence for optimizing neoadjuvant treatment strategies for this population.
详细描述
Patients with locally advanced rectal adenocarcinoma characterized by proficient mismatch repair or microsatellite stability (pMMR/MSS) generally derive limited benefit from immune checkpoint inhibitor monotherapy. Metabolic interventions may enhance the efficacy of chemotherapy and immunotherapy by modulating tumor metabolism and the tumor immune microenvironment. High-dose vitamin C has multitarget antitumor effects. Preclinical evidence suggests that it may activate the AMPK pathway, downregulate PD-L1 expression in colorectal cancer cells, and promote T-cell infiltration into the tumor microenvironment, thereby providing a mechanistic rationale for its combination with PD-1 blockade. In the phase III VITALITY trial, high-dose intravenous vitamin C combined with chemotherapy did not significantly improve progression-free survival in the overall population with metastatic colorectal cancer; however, a prespecified subgroup analysis demonstrated prolonged progression-free survival among patients with RAS-mutant tumors. A ketogenic diet may also exert antitumor effects by altering glucose availability, cellular energy metabolism, and the immune microenvironment. Emerging evidence suggests that dietary patterns, including high-fiber diets in patients receiving immunotherapy and ketogenic diets in those receiving chemotherapy, may be associated with improved treatment responses, although these findings require prospective validation. Therefore, this study aims to investigate whether adding a ketogenic diet and/or high-dose intravenous vitamin C to short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with the PD-1 monoclonal antibody serplulimab can improve the pathological complete response and organ preservation rates in patients with locally advanced pMMR/MSS rectal adenocarcinoma. The efficacy and safety of four treatment strategies-no metabolic intervention, a ketogenic diet alone, high-dose intravenous vitamin C alone, and their combination-will be evaluated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Histologically confirmed rectal adenocarcinoma.
- •Age 18-80 years.
- •Immunohistochemical examination of biopsy specimens indicating proficient mismatch repair (pMMR), or microsatellite-stable (MSS) status.
- •4. Clinical stage cT3-T4N0 or cTxN+.
- •The lower margin of the rectal tumor is ≤10 cm from the anal verge.
- •No distant metastases, as confirmed by contrast-enhanced CT of the chest, abdomen, and pelvis and pelvic MRI before treatment.
- •7. No evidence of intestinal obstruction, or resolution of obstruction following diverting stoma surgery.
- •8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Adequate peripheral blood counts and hepatic and renal function, as defined by the following laboratory values measured within 15 days before treatment initiation:
- •White blood cell count (WBC) ≥3.0 × 10⁹/L or absolute neutrophil count (ANC) ≥1.5 × 10⁹/L;
- •Hemoglobin (HGB) ≥80 g/L;
- •Platelet count (PLT) ≥100 × 10⁹/L;
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3.0 × the upper limit of normal (ULN);
- •Total bilirubin (TBIL) <1.5 × ULN;
- •Serum creatinine (CREAT) <1.5 × ULN.
- •No prior chemotherapy or radiotherapy.
- •No prior treatment with biological agents (e.g., monoclonal antibodies), immunotherapy (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibodies), or other investigational agents.
- •12. Not pregnant or breastfeeding. Participants must use effective contraception during the study and for 6 months after the final dose of study treatment.
- •13. Written informed consent has been provided.
排除标准
- •Arrhythmia requiring antiarrhythmic therapy, except for beta-blockers or digoxin; symptomatic coronary artery disease; myocardial ischemia, including myocardial infarction within the previous 6 months; or congestive heart failure greater than New York Heart Association (NYHA) class II.
- •Severe hypertension that is inadequately controlled with medication.
- •A history of human immunodeficiency virus (HIV) infection or active chronic hepatitis B or C infection with a high viral DNA copy number.
- •Active tuberculosis (TB), current anti-tuberculosis treatment, or receipt of anti-tuberculosis treatment within 1 year before screening.
- •Other active, clinically serious infections according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.
- •Preoperative evidence of distant metastases outside the pelvis.
- •Cachexia or decompensated organ function.
- •Prior pelvic or abdominal radiotherapy.
- •Multiple primary colorectal cancers.
- •Confirmed glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- •Seizures requiring treatment, such as corticosteroid or antiepileptic therapy.
- •A history of another malignancy within the previous 5 years, except for cured cervical carcinoma in situ or basal cell carcinoma of the skin.
- •Substance abuse or any medical, psychological, or social condition that may interfere with participation in the study or the evaluation of study results.
- •Any active autoimmune disease or history of autoimmune disease, including but not limited to interstitial pneumonitis, uveitis, enteritis, hepatitis, hypophysitis, nephritis, hyperthyroidism, or hypothyroidism. Participants with vitiligo or childhood asthma that has completely resolved and requires no intervention in adulthood may be enrolled; participants with asthma requiring medical intervention with bronchodilators are excluded.
- •Receipt of any vaccine against an infectious disease, such as an influenza or varicella vaccine, within 4 weeks before enrollment.
- •A concomitant condition requiring long-term immunosuppressive therapy or systemic or topical corticosteroids at immunosuppressive doses, defined as >10 mg/day of prednisone or an equivalent corticosteroid.
- •Gastrointestinal disorders, such as an active gastric or duodenal ulcer, ulcerative colitis, or an unresected tumor with active bleeding; any other condition that may cause gastrointestinal bleeding or perforation; or an unhealed gastrointestinal perforation following surgery.
- •Known or suspected hypersensitivity to any study drug or to any medication administered in connection with this study.
- •Any unstable condition or other circumstance that may compromise participant safety or treatment compliance.
- •Pregnant or breastfeeding women, or women of childbearing potential who are not using adequate contraception.
- •Refusal to provide written informed consent.
研究组 & 干预措施
Short-Course Radiotherapy + mFOLFOX6 + PD-1
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen and PD-1 monoclonal antibody. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody at two-week intervals. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: PD-1 monoclonal antibody (Drug)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, Vitamin C and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Surgical resection (Procedure)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, Vitamin C and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Vitamin C (Drug)
Short-Course Radiotherapy + mFOLFOX6 + PD-1
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen and PD-1 monoclonal antibody. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody at two-week intervals. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Short-Course Radiotherapy (Radiation)
Short-Course Radiotherapy + mFOLFOX6 + PD-1
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen and PD-1 monoclonal antibody. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody at two-week intervals. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: mFOLFOX6 regimen (Combination Product)
Short-Course Radiotherapy + mFOLFOX6 + PD-1
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen and PD-1 monoclonal antibody. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody at two-week intervals. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Surgical resection (Procedure)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Short-Course Radiotherapy (Radiation)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and Vitamin C. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Short-Course Radiotherapy (Radiation)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: PD-1 monoclonal antibody (Drug)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: mFOLFOX6 regimen (Combination Product)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Ketogenic Diet (Behavioral)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Surgical resection (Procedure)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and Vitamin C. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: PD-1 monoclonal antibody (Drug)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and Vitamin C. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: mFOLFOX6 regimen (Combination Product)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and Vitamin C. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Surgical resection (Procedure)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, Vitamin C and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Short-Course Radiotherapy (Radiation)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, Vitamin C and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: PD-1 monoclonal antibody (Drug)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, Vitamin C and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: mFOLFOX6 regimen (Combination Product)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Ketogenic Diet + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, Vitamin C and daily ketogenic diet. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. After completing radiotherapy, patients initiate a ketogenic dietary intervention and, at least 7 days later, receive six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. The ketogenic dietary intervention continues until the completion of neoadjuvant treatment. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Ketogenic Diet (Behavioral)
Short-Course Radiotherapy + mFOLFOX6 + PD-1 + Vitamin C
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with 6 cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody and Vitamin C. Initially, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients complete 6 cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and at two-week intervals, together with intravenous vitamin C at 1.5 g/kg/day on three consecutive days (Days 1-3) of each cycle. Surgery is performed 2 weeks after the completion of the last cycle of chemotherapy.
干预措施: Vitamin C (Drug)
结局指标
主要结局
pCR rate
时间窗: 1 year
Pathological complete response rate, ypT0N0 for TME surgery and ypT0rN0 for local excision
次要结局
- TRG(1 year)
- Adverse Events Associated with Neoadjuvant Therapy(1 year)
- MPR(1 year)
- Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate(1 year)
- R0 resection rate(1 year)
- 3 years DFS Rate(3 years)
- 3 years OS rate(3 years)
研究者
Jun Huang
Professor
Sixth Affiliated Hospital, Sun Yat-sen University