Clinical trial NCT06594692: Node-Sparing Short-Course Radiation with CAPOX and Sintilimab for MSS Locally Advanced Colon Cancer: a Randomized, Prospective, Multicenter Study
Official title: Node-sparing Modified Short-Course Radiation Combined with CAPOX and Sintilimab for MSS Locally Advanced Colon Cancer : a Randomized, Prospective, Multicenter, Open-label Clinical Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Microsatellite Stable (MSS) Colon Cancer
Locally Advanced Colon Cancer
Keywords: Locally Advanced Colon Cancer
Microsatellite Stable (MSS) Colon Cancer
Node-Sparing Radiotherapy
Short-Course Radiotherapy
Sintilimab
Lead sponsor: Sir Run Run Shaw Hospital
Sponsor class: OTHER
First posted: 2024-09-19
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the use of node-sparing short-course radiotherapy combined with chemotherapy and Sintilimab, or chemotherapy alone, as neoadjuvant therapy for MSS-type locally advanced colon cancer. The goal is to explore the efficacy and safety of combining node-sparing short-course radiotherapy with chemotherapy and immunotherapy in the neoadjuvant setting for MSS-type locally advanced colon cancer, while also investigating the specific role of regional lymph nodes in tumor immunotherapy.

Detailed description: Colorectal cancer is currently one of the most common malignant tumors in China. According to the latest data released by the National Cancer Center, it ranks second in incidence and fourth in mortality among all cancer types. Statistics indicate that approximately 50% of colon cancer patients in China are in stages II-III. Currently, adjuvant chemotherapy regimens containing oxaliplatin and 5-fluorouracil are the standard treatment for stage III and high-risk stage II colon cancer patients. However, under standard treatment protocols, the 5-year disease-free survival (DFS) rate for stage III colon cancer is less than 64%, with a recurrence rate exceeding 20%. Patients with higher T and N stages face a significantly increased risk of recurrence, severely impacting survival rates and imposing a substantial burden on both the healthcare system and society.

Neoadjuvant chemotherapy, which is administered before surgery, offers several theoretical advantages, including shrinking the primary tumor to improve surgical resection rates, reducing intraoperative tumor cell spread, and eliminating micrometastases and subclinical lesions to lower the risk of postoperative metastasis. However, data on neoadjuvant chemotherapy for locally advanced colon cancer remains limited. The FOxTROT study found that preoperative neoadjuvant chemotherapy significantly reduced the 2-year recurrence rate for locally advanced colon cancer, achieved tumor downstaging, and provided a 4% pathological complete response (pCR) rate. This study also demonstrated a strong correlation between pathological response to neoadjuvant therapy and recurrence risk, with patients achieving pCR or major pathological response (mPR) having significantly lower recurrence rates.

Recent studies have shown that combining immunotherapy with radiotherapy has a synergistic effect, even in MSS-type colorectal cancer patients. Radiotherapy can induce immunogenic cell death, releasing tumor-associated antigens and enhancing the function of dendritic cells, thereby increasing T-cell infiltration. Moreover, chemotherapy can alter the tumor microenvironment, promote angiogenesis, and improve oxygen distribution, further enhancing the efficacy of radiotherapy. One prospective phase II clinical trial involving locally advanced rectal cancer patients showed promising results, with a pCR rate of 46.2% in patients with proficient mismatch repair (pMMR), suggesting a favorable response to neoadjuvant therapy.

Lymph nodes, as secondary lymphoid organs, play a crucial role in tumor diagnosis and treatment. Recent preclinical studies have shown that tumor-draining lymph nodes (TDLNs) are essential in antigen activation and effector T-cell differentiation. On the other hand, tertiary lymphoid structures (TLS), which are organized immune cell aggregates formed in non-lymphoid tissues, have been associated with improved prognosis in cancer patients. However, the role of TDLNs in immunotherapy remains underexplored.

Based on these findings, the research team hypothesizes that tumor-draining lymph nodes play a positive role in immunotherapy response, and sparing these nodes during radiotherapy may enhance the efficacy of immunotherapy for MSS-type colorectal cancer. The team previously conducted a phase II clinical study (NCT04503694) investigating the safety and efficacy of node-sparing short-course radiotherapy combined with CAPOX chemotherapy and PD-1 inhibitors in MSS-type locally advanced rectal cancer. Results showed a 100% response rate to neoadjuvant therapy, with a pCR rate of 78.8% and a major pathological response (mPR) rate of 91%, while maintaining a high rate of organ preservation.

Given the high recurrence rates and treatment challenges associated with locally advanced colon cancer, and building on the promising results of previous studies, the research team intends to conduct the mRCAT-C study. This study aims to explore the clinical efficacy and safety of a node-sparing short-course radiotherapy combined with immunotherapy as a neoadjuvant treatment for MSS-type locally advanced colon cancer.

Eligibility criteria: Inclusion Criteria:

* 1. Patients willing to undergo neoadjuvant treatment. 2. Age ≥ 18 years. 3. Tumor confirmed by colonoscopy and enhanced abdominal CT to be ≥ 12 cm from the anal verge.

  4. Histologically diagnosed adenocarcinoma; genetic testing indicates MSI-L or MSS, or immunohistochemistry from tumor biopsy shows pMMR (all four proteins-MSH1, MSH2, MSH6, and PMS2-are positive).

  5. Clinical staging by enhanced abdominal CT evaluates as cT3-4N0-2M0. 6. ECOG performance status score of 0-1. 7. No prior treatment with anti-tumor, immunotherapy, or abdominal radiation therapy before enrollment.

  8. Blood test results (without transfusion within 14 days and no use of granulocyte colony-stimulating factor or other hematopoietic stimulators within 7 days before the lab test):
  1. White blood cell count ≥ 3.5 × 10\^9/L, absolute neutrophil count ≥ 1.5 × 10\^9/L, platelet count ≥ 100 × 10\^9/L, hemoglobin concentration ≥ 9 g/dL;
  2. Liver function tests (bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 5 × ULN);
  3. Renal function (serum creatinine ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 50 mL/min);
  4. Coagulation (INR ≤ 1.5 × ULN, PT and APTT ≤ 1.5 × ULN);
  5. Thyroid function: TSH ≤ upper limit of normal (ULN); if abnormal, FT3 and FT4 levels must be evaluated, and if FT3 and FT4 are normal, the patient is eligible.

     9. Voluntary participation with a signed informed consent form.

     Exclusion Criteria:
* 1. History of other malignancies within the past 5 years. 2. Patients with metastases in other locations (stage IV). 3. Patients with MSI-H or dMMR. 4. Patients with conditions such as bowel obstruction, perforation, or bleeding requiring emergency surgery.

  5. Known allergy to the study drug or any of its excipients. 6. Patients with any unstable systemic diseases, including but not limited to severe infections, uncontrolled diabetes, uncontrolled hypertension, unstable angina, cerebrovascular accidents or transient ischemic attacks, myocardial infarction, congestive heart failure, or severe illnesses requiring medication (such as arrhythmias, liver, kidney, or metabolic diseases) that are life-threatening.

  7. History of active autoimmune diseases requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within the last 2 years. Replacement therapies (e.g., thyroid hormone, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency) are not considered systemic treatments.

  8. Known history of HIV infection or acquired immunodeficiency syndrome (AIDS). 9. Receipt of any investigational drug (including immunotherapy) or participation in another interventional clinical study within 30 days before screening.

  10. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study; men or women unwilling to use effective contraception during the study.

  11. Vulnerable populations, including those with mental illness, cognitive impairment, or critically ill patients.

  12. Any other conditions deemed inappropriate for participation by the investigator.

Primary outcomes:
measure: pathological complete response rate
timeFrame: 2 weeks after surgery
Secondary outcomes:
measure: R0 resection rate
timeFrame: 2 weeks after surgery
measure: Tumor downstaging rate
timeFrame: 2 weeks after surgery
measure: The 3-year Event-Free Survival
timeFrame: 3 years post-treatment
measure: Objective Response Rate
timeFrame: 2 weeks after surgery
measure: The 3-year Local Recurrence Rate
timeFrame: 3 years post-treatment
measure: 3-year Disease-Free Survival
timeFrame: 3 years post-treatment
measure: 3-year Overall Survival
timeFrame: 3 years post-treatment
measure: The incidence of grade III/IV adverse events
timeFrame: 2 weeks after surgery
measure: EORTCQLQ-C30
timeFrame: 3 years post-treatment
measure: EORTCQLQ-CR29
timeFrame: 3 years post-treatment
Other outcomes:
Locations:
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University
Study officials:
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