Rectal Adenocarcinoma, High-Risk Cancer, MSS
Conditions
Keywords
Targeting Therapy, Immunotherapy, Short-Course Radiotherapy, Ketogenic Diet, High-dose Intravenous Vitamin C
Brief summary
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.
Detailed description
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.
Interventions
RADIATIONShort-Course Radiotherapy
Patients undergo SCRT at a dose of 5Gy × 5 fractions
DRUGPD-1 monoclonal antibody
Patients receive six cycles of immunotherapy with serplulimab injection, a PD-1 monoclonal antibody, at a fixed dose of 200 mg per cycle.
COMBINATION_PRODUCTmFOLFOX6 regimen
Patients receive six cycles of the mFOLFOX6 regimen, consisting of oxaliplatin (85 mg/m²) and leucovorin (200 mg/m²) administered intravenously over 2 hours, followed by a bolus of fluorouracil (400 mg/m²) and a continuous infusion of fluorouracil (2,400 mg/m²) over 46 hours.
BEHAVIORALKetogenic Diet
A modified Atkins diet (MAD) is used, with the goal of maintaining nutritional ketosis, defined as a blood β-hydroxybutyrate (BHB) level of 1.5-3.0 mmol/L. The ketogenic dietary intervention begins after completion of SCRT and continues throughout six cycles of mFOLFOX6 chemotherapy and immunotherapy until the completion of neoadjuvant treatment.
PROCEDURESurgical resection
Surgery either local excition or total mesorectal excision is performed 2 weeks after the completion of neoadjuvant therapy.
DRUGVitamin C
Vitamin C is administered intravenously at a dose of 1.5 g/kg/day, diluted in 250-500 mL of normal saline, over 2 hours for 3 consecutive days (Days 1-3). Each treatment cycle is repeated every 2 weeks and synchronized with the neoadjuvant treatment cycle.
Sponsors
Sixth Affiliated Hospital, Sun Yat-sen University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective, open-label, phase II study with a 2 × 2 factorial design. All participants receive short-course radiotherapy followed by six cycles of mFOLFOX6 chemotherapy combined with a PD-1 monoclonal antibody. Participants are assigned to one of four groups: no metabolic intervention, a ketogenic diet alone, high-dose intravenous vitamin C alone, or the combination of a ketogenic diet and high-dose intravenous vitamin C. A Simon optimal two-stage design is applied separately to each of the three experimental groups.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1\. Histologically confirmed rectal adenocarcinoma. 2. Age 18-80 years. 3. Immunohistochemical examination of biopsy specimens indicating proficient mismatch repair (pMMR), or microsatellite-stable (MSS) status. 4\. Clinical stage cT3-T4N0 or cTxN+. 5. The lower margin of the rectal tumor is ≤10 cm from the anal verge. 6. 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 0-1. 9. 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. 10. No prior chemotherapy or radiotherapy. 11. 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.
Exclusion criteria
1. 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. 2. Severe hypertension that is inadequately controlled with medication. 3. A history of human immunodeficiency virus (HIV) infection or active chronic hepatitis B or C infection with a high viral DNA copy number. 4. Active tuberculosis (TB), current anti-tuberculosis treatment, or receipt of anti-tuberculosis treatment within 1 year before screening. 5. Other active, clinically serious infections according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. 6. Preoperative evidence of distant metastases outside the pelvis. 7. Cachexia or decompensated organ function. 8. Prior pelvic or abdominal radiotherapy. 9. Multiple primary colorectal cancers. 10. Confirmed glucose-6-phosphate dehydrogenase (G6PD) deficiency. 11. Seizures requiring treatment, such as corticosteroid or antiepileptic therapy. 12. A history of another malignancy within the previous 5 years, except for cured cervical carcinoma in situ or basal cell carcinoma of the skin. 13. Substance abuse or any medical, psychological, or social condition that may interfere with participation in the study or the evaluation of study results. 14. 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. 15. Receipt of any vaccine against an infectious disease, such as an influenza or varicella vaccine, within 4 weeks before enrollment. 16. 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. 17. 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. 18. Known or suspected hypersensitivity to any study drug or to any medication administered in connection with this study. 19. Any unstable condition or other circumstance that may compromise participant safety or treatment compliance. 20. Pregnant or breastfeeding women, or women of childbearing potential who are not using adequate contraception. 21. Refusal to provide written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| pCR rate | 1 year | Pathological complete response rate, ypT0N0 for TME surgery and ypT0rN0 for local excision |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Associated with Neoadjuvant Therapy | 1 year | Incidence of adverse events related to neoadjuvant therapy as assessed by CTCAE v5.0 |
| MPR | 1 year | Major pathological response rate |
| Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate Neoadjuvant therapy completion rate | 1 year | Completion rate of neoadjuvant therapy |
| R0 resection rate | 1 year | R0 resection rate in participants |
| TRG | 1 year | Tumor regression grade |
| 3 years DFS Rate | 3 years | 3 years Disease Free Survival Rate |
| 3 years OS rate | 3 years | 3 years Overall Survival Rate |
Countries
China
Contacts
CONTACTJun Huang, PhD.
CONTACTFang He, MD.
STUDY_CHAIRJun Huang, PhD.
6th Affliated Hospital of Sun Yat-sen University
PRINCIPAL_INVESTIGATORGuohui Wan, PhD.
School of Pharmaceutical Sciences, Sun Yat-Sen University
Outcome results
None listed