Colorectal Cancer, Relapse
Conditions
Brief summary
Approximately 20-50% of patients with colorectal cancer (CRC) develop distant metastasis after curative surgery, and those with early relapse within one year of completing adjuvant chemotherapy (XELOX or FOLFOX) have a particularly poor prognosis and limited treatment options. Standard second-line therapy with FOLFIRI plus targeted therapy (bevacizumab or cetuximab) often yields suboptimal outcomes in this population. Moreover, over 95% of these patients have pMMR/MSS tumors, which are inherently resistant to immune checkpoint inhibitor monotherapy. This phase II, prospective, randomized trial aims to evaluate the efficacy and safety of adding serplulimab, a PD-1 inhibitor, to second-line chemotherapy plus targeted therapy in patients with early-relapse CRC after adjuvant chemotherapy. Eligible patients with pMMR/MSS or MSI-L tumors will be randomly assigned (1:1) to either the experimental arm (serplulimab plus FOLFIRI and targeted therapy) or the control arm (FOLFIRI plus targeted therapy alone). Randomization is stratified by primary tumor location (left vs. right colon), initial disease status (liver-only vs. extrahepatic metastasis), and RAS status (wild-type vs. mutant). A total of 40 patients (20 per arm) will be enrolled using a Pick-the-Winner design. The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), overall survival (OS), R0 resection rate, and safety (NCI-CTCAE v5.0). Exploratory biomarker analyses in tumor tissue and blood (e.g., PD-L1 expression, tumor mutational burden, lymphocyte subsets, cytokines, TCR sequencing, circulating tumor DNA, and gut microbiome) will be performed to identify potential predictors of response and resistance. This is the first prospective randomized study specifically targeting early-relapse CRC after adjuvant chemotherapy. The findings will provide high-level evidence on whether adding PD-1 blockade to standard chemo-targeted therapy can improve outcomes in this high-risk, understudied population and may inform future phase III trials.
Interventions
DRUGSerplulimab
Serplulimab: 3 mg/kg intravenously on Day 1, repeated every 2 weeks
DRUGSecond-Line Chemo/Targeted Therapy
Left-sided, RAS wild-type Treatment Regimen: Cetuximab 400 mg/m², intravenous infusion, first infusion over \>2 hours, then 250 mg/m² intravenous infusion over ≥60 minutes, repeated weekly; FOLFIRI: Irinotecan 180 mg/m², intravenous infusion over 90 minutes, Day 1; Leucovorin (LV) 400 mg/m², intravenous infusion over 2 hours, Day 1; 5-FU 400 mg/m², intravenous bolus, Day 1; followed by 2400 mg/m² infusion over 46-48 hours; Repeated every 2 weeks Right-sided, RAS mutant Treatment Regimen: Bevacizumab 5 mg/kg, intravenous infusion, Day 1, repeated every 2 weeks FOLFIRI: Irinotecan 180 mg/m², intravenous infusion over 90 minutes, Day 1; Leucovorin (LV) 400 mg/m², intravenous infusion over 2 hours, Day 1; 5-FU 400 mg/m², intravenous bolus, Day 1; followed by 2400 mg/m² infusion over 46-48 hours; Repeated every 2 weeks
Sponsors
Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Age ≥18 years, male or female. Histologically confirmed early relapse (within 1 year after surgery, UICC stage IV) of colorectal cancer after adjuvant chemotherapy, with initially unresectable metastatic lesions or refusal of surgery. Have received standard postoperative adjuvant chemotherapy (XELOX or FOLFOX). Before enrollment, tumor tissue tested by immunohistochemistry as pMMR, or by PCR or NGS as MSS or MSI-L. At least one measurable tumor lesion according to RECIST 1.1 criteria. ECOG performance status 0-1. Life expectancy ≥3 months. Adequate organ function: 1. Neutrophils ≥1.5 × 10⁹/L; platelets ≥100 × 10⁹/L; hemoglobin ≥9 g/dL; serum albumin ≥3 g/dL. 2. Thyroid-stimulating hormone (TSH) ≤ upper limit of normal (ULN), with T3 and T4 within normal range. 3. Bilirubin ≤1.5 × ULN; ALT and AST ≤2 × ULN. 4. Serum creatinine ≤1.5 × ULN, creatinine clearance ≥60 mL/min. 5. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN, unless the patient is receiving anticoagulant therapy and PT is within the expected therapeutic range for anticoagulation. 6. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Female patients of childbearing potential must have a negative pregnancy test. Female patients not of childbearing potential, fertile male patients, and female patients of childbearing potential at risk of pregnancy must agree to use adequate contraception throughout the study and for 12 months after the last dose of study treatment. Signed and dated written informed consent indicating that the patient has been informed of all relevant aspects of the study. Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Exclusion criteria
Pathologically diagnosed other intestinal tumors, such as gastrointestinal stromal tumors. RAS mutation status not tested. Tumor tissue tested by immunohistochemistry as dMMR, or by PCR or NGS as MSI-H. Metastatic lesions are resectable, or the patient wishes to undergo metastasectomy. Uncontrolled active bleeding from the primary tumor or intestinal obstruction. Contraindications to immune checkpoint inhibitor therapy. Hypersensitivity to study drugs or their excipients. Prior or concurrent other malignancy, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ, and papillary thyroid carcinoma. Active autoimmune disease or history of autoimmune disease (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); excluding autoimmune-mediated hypothyroidism treated with stable doses of thyroid replacement hormone, type I diabetes mellitus treated with stable doses of insulin, vitiligo, or childhood asthma/allergy that has resolved and requires no intervention in adulthood. History of immunodeficiency, including HIV positivity, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation. History of interstitial lung disease or non-infectious pneumonitis. Active pulmonary tuberculosis infection by history or CT scan, or history of active pulmonary tuberculosis infection within 1 year before enrollment, or history of active pulmonary tuberculosis infection more than 1 year prior without adequate treatment. Active hepatitis B (HBV DNA ≥2000 IU/mL or 10⁴ copies/mL) or hepatitis C (positive HCV antibody with HCV-RNA above the lower limit of detection of the assay). Severe cardiac, pulmonary, renal, or hepatic dysfunction. Hypertension that cannot be adequately controlled with antihypertensive medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg). History of psychotropic substance abuse, alcoholism, or drug addiction. Other factors that may affect patient safety or trial compliance as judged by the investigator, such as serious diseases requiring concomitant treatment (including psychiatric disorders), serious laboratory abnormalities, or other family or social factors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | 12 months | Progression-free survival (PFS) is defined as the time from randomization to the first documented tumor progression or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR = CR + PR) | 12 months | Objective response rate (ORR = CR + PR): The proportion of patients whose best overall response is complete response or partial response. |
| Disease control rate (DCR = CR + PR + SD) | 12 months | Disease control rate (DCR = CR + PR + SD): The proportion of patients whose best overall response is complete response, partial response, or stable disease. |
| R0 resection rate | 12 months | R0 resection rate: The proportion of tumors in which pathological examination confirms no residual cancer cells at the surgical margin (resection margin) after surgery. |
| Overall survival (OS) | 36 months | Overall survival (OS): The time from randomization to death from any cause. |
Countries
China
Contacts
CONTACTQingguo Li, M.D.
Outcome results
None listed