Rectal Cancer Patients, Locally Advanced Rectal Cancer (LARC)
Conditions
Brief summary
This is a prospective, randomized, multicenter phase II trial evaluating neoadjuvant CAPOX chemotherapy combined with the PD-1 inhibitor serplulimab administered either before or after short-course radiotherapy (SCRT) in patients with locally advanced rectal cancer. The primary endpoint is the complete response (CR) rate, defined as pathological complete response (pCR) plus clinical complete response (cCR). Secondary endpoints include safety, perioperative outcomes, survival, recurrence patterns, and integrated multi-omics analyses of paired tumor samples. The study aims to determine the optimal sequencing strategy and identify immune microenvironmental biomarkers predictive of response.
Detailed description
Colorectal cancer is one of the most common malignancies worldwide, with rectal cancer accounting for over 700,000 new cases annually. In China, colorectal cancer ranks second in incidence and fourth in cancer-related mortality. More than half of newly diagnosed patients present with locally advanced rectal cancer (LARC), requiring multimodality therapy. Neoadjuvant approaches have improved local control and compliance compared with adjuvant strategies, but conventional fluoropyrimidine-based chemoradiotherapy achieves limited pathological complete response (pCR) rates of \ 15% and distant metastasis rates remain high. Total neoadjuvant therapy (TNT), which delivers systemic chemotherapy before surgery, has become the new standard of care, supported by phase III trials such as RAPIDO, PRODIGE-23, and STELLAR, which demonstrated improved pCR and survival. However, the optimal sequencing of chemotherapy and radiotherapy-induction versus consolidation-remains uncertain, with each approach offering distinct advantages. Immunotherapy targeting the PD-1/PD-L1 axis has transformed cancer treatment and shows dramatic efficacy in mismatch repair-deficient (dMMR)/MSI-H colorectal cancer, but the vast majority of rectal cancers are mismatch repair-proficient (pMMR)/microsatellite stable (MSS), where single-agent immunotherapy is ineffective. Preclinical and translational studies suggest radiotherapy enhances antitumor immunity by promoting antigen release, immunogenic cell death, and T cell infiltration. Several phase II/III studies have shown promising efficacy of combining SCRT, chemotherapy, and PD-1 inhibitors, with complete response (CR) rates exceeding 40%. Building on these findings, this randomized phase II trial (NeoCSR-Omics) will compare induction immunochemotherapy followed by SCRT versus SCRT followed by consolidation immunochemotherapy in LARC patients. The primary endpoint is CR rate, defined as pCR plus cCR. Secondary endpoints include safety, perioperative outcomes, survival, recurrence, and quality of life. Fresh and surgical tumor samples will undergo single-cell RNA sequencing and TCR/BCR sequencing to explore how treatment sequencing reshapes the tumor microenvironment and to identify biomarkers predictive of response. This study aims to determine the optimal sequence of immunochemotherapy and radiotherapy and provide mechanistic insights to guide precision treatment in locally advanced rectal cancer.
Interventions
RADIATIONradiotherapy
1. Short-course pelvic radiotherapy 2. IMRT/VMAT/TOMO, 25 Gy in 5 fractions (5 Gy per fraction)
* Capecitabine: 1000 mg/m² orally BID, D1-14, every 3 weeks * Oxaliplatin: 130 mg/m² IV, D1, every 3 weeks
DRUGSerplulimab
Serplulimab (HLX10): 300 mg IV, D1, every 3 weeks
Sponsors
Chongqing University Cancer Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-70 years, any sex. * Clinical stage II/III rectal adenocarcinoma (cT3-T4N0 or cT2-T4N+, M0) according to AJCC 8th edition. * Tumor located ≤10 cm from anal verge (confirmed by colonoscopy or digital rectal exam). * Histologically confirmed rectal adenocarcinoma. * ECOG performance status 0-1. * Adequate organ function: * Hemoglobin ≥90 g/L; WBC ≥3.5×10⁹/L; ANC ≥1.5×10⁹/L; Platelets ≥100×10⁹/L. * Serum creatinine, BUN ≤1.0×ULN. * ALT, AST, ALP ≤1.5×ULN; Total bilirubin ≤1.5×ULN. * Negative urine protein; normal coagulation. * No known allergy to fluoropyrimidines or platinum. * No prior surgery (except diverting colostomy), chemotherapy, or radiotherapy for primary rectal cancer. * No prior pelvic radiotherapy. * Signed written informed consent.
Exclusion criteria
* Prior treatment with PD-1/PD-L1 or CTLA-4 inhibitors, or other investigational immunotherapies. * Active autoimmune disease (e.g., Crohn's disease, ulcerative colitis, rheumatoid arthritis, scleroderma, SLE, vasculitis). * Symptomatic interstitial lung disease or active pneumonia. * GI conditions increasing risk of perforation (e.g., active diverticulitis, abscess, obstruction). * History of other malignancies, except cured non-melanoma skin cancer or in situ cervical cancer. * Active infections, uncontrolled heart failure, recent myocardial infarction (\<6 months), unstable angina, or severe arrhythmia. * Other uncontrolled disease or condition that may interfere with study participation. * Pregnancy or lactation. * Known immunodeficiency (e.g., HIV) or history of organ/allo-HSCT transplantation. * Active HBV (HBV DNA ≥2000 IU/mL), HCV infection, or active tuberculosis. * Receipt of cancer vaccines or live vaccines within 4 weeks prior to enrollment (seasonal inactivated influenza vaccines allowed). * Concurrent use of other investigational agents, long-term corticosteroids, or immunosuppressants. * Psychiatric disorders, substance abuse, or social conditions limiting compliance. * Known allergy or contraindication to study drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) | one year | CR is defined as the proportion of patients achieving either pathological complete response (pCR, no residual viable tumor in the resected specimen) after radical surgery or clinical complete response (cCR, absence of residual tumor confirmed by endoscopy, digital rectal examination, and pelvic MRI in patients managed with organ preservation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-related adverse events | three months | — |
| Incidence of surgical complications | 30 days | — |
| Changes in immune microenvironment | Baseline, after neoadjuvant therapy, and at surgery (up to 6 months) | Immune profiling of tumor and stromal compartments using histopathology and multi-omics analyses to assess differences between treatment arms and correlation with efficacy. |
| Radical resection (R0) | one year | — |
| Overall survival rate | three year | — |
| Disease-free survival rate | three year | — |
| Locoregional recurrence rate | three year | — |
| Distance metastasis rate | three year | — |
Countries
China
Contacts
CONTACTQishuai Guo
Outcome results
None listed