Intestinal Microbiota Transplantation, Radiochemotherapy and Sintilimab in Localized Advanced Colon Cancer

Phase 4

• Conditions: Localized Advanced Rectal Adenocarcinoma
• Interventions: Drug: Sintilimab plus Chemotherapy; Drug: Intestinal microbiota capsules; Radiation: Standard Long Course Radiotherapy; Procedure: Total mesorectal excision

• Registration Number: NCT06931808
• Lead Sponsor: First Affiliated Hospital of Ningbo University

Brief Summary

The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by total mesorectal excision. While Immune checkpoint inhibitors are promising in the treatment of various cancers, the combination of radiotherapy and immunotherapy still lacks high-level evidence-based medicine, and the efficacy is still limited in rectal cancer.

Thus, we designed a study on the efficacy and safety of intestinal microbiota transplantation combined with synchronous radiochemotherapy and immune checkpoint inhibitor xindilimab neoadjuvant therapy for locally advanced rectal cancer.

Detailed Description

The incidence rate of colorectal cancer (CRC) ranks among the top three most common cancers in the world, while the mortality rate ranks among the top two. Early symptoms of rectal cancer are not obvious, and about 60% of patients are diagnosed with locally advanced rectal cancer. The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by total mesorectal excision. However, the response of patients to radiotherapy showed significant heterogeneity, with pathological complete response rates (pCR) ranging from 6% to 39%. In addition, a significant proportion of LARC patients (20% -40%) do not respond to preoperative radiotherapy (preRT). Therefore, it is crucial to find ways to alleviate radiation resistance within tumors.

Immune checkpoint inhibitors (ICIs) are increasingly being used in various solid tumors. However, immunotherapy in the field of CRC has always been distinct, with patients with mismatch repair defects (dMMR) or high microsatellite instability (MSI-H) (accounting for 5% -15% of all CRCs) having a higher tumor mutation burden (TMB) and more tumor infiltrating lymphocytes (TILs), making them the absolute dominant population for immunotherapy; However, patients with microsatellite stability (MSS) or normal mismatch repair (pMMR) have poor immune therapy efficacy. At present, radiotherapy is widely regarded as a mechanism that triggers local and systemic immune responses, providing a theoretical basis for the combination of radiotherapy and immunotherapy (iRT). In 2022, the VOLTAGE-A study reported the addition of nivolumab treatment after long-term synchronous chemoradiotherapy. The results showed that the major pathological response (MPR) rate and pCR rate in 37 MSS LARC patients after surgery were 38% and 30%, respectively. In addition, multiple studies have conducted similar explorations with different methods. Overall, these studies have achieved certain therapeutic effects, with pCR rates ranging from 37.5% to 57.1%. However, the combination of radiotherapy and immunotherapy still lacks high-level evidence-based medicine, and the efficacy is still limited.

The gut microbiota is a complex microbial community closely related to the occurrence and development of rectal cancer. Previous studies have shown that gut microbiota can predict response to neoadjuvant radiotherapy, improve treatment response, and reduce treatment toxicity. In addition, it has been confirmed that the gut microbiota can reshape the tumor immune microenvironment (TiME), thereby affecting the response to ICIs. The results of two Phase I trials indicate that gut microbiota transplantation (FMT) derived from responders effectively reversed immune resistance in melanoma, laying the foundation for the clinical application of FMT in cancer immunotherapy. In a phase II study, a total of 20 MSS mCRC patients were enrolled and received FMT combined with trastuzumab and furosemide as third line or above treatment. The median PFS was 9.6 months (95% CI 4.1-15.1) and the median OS was 13.7 months (95% CI 9.3-17.7), with controllable side effects, demonstrating the potential of FMT in the field of rectal cancer.

Study Timeline

• Study Start: 2025-03-01
• Study First Submitted: 2025-03-15
• Status Verified: 2025-04
• Study First Submitted QC: 2025-04-09
• Last Update Submitted: 2025-04-09
• Study First Posted: 2025-04-17
• Last Update Posted: 2025-04-17
• Primary Completion: 2026-03-01
• Study Completion: 2028-08-01

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

• 1. Other malignant tumors, including rectal cancer with other pathological types within 5 years; 2. Not using probiotics in the past 2 months; 3. Severe damage to the intestinal barrier, such as sepsis, active gastrointestinal bleeding, perforation, etc.; 4. Weight loss of ≥ 20% within 90 days; 5. Poor nutritional status or PG-SGA score ≥ 9; 6. Severe and/or uncontrolled illnesses.

  2. Poor blood pressure control (systolic blood pressure ≥ 150mmHg or diastolic blood pressure ≥ 100mmHg)

  3. ≥ grade 2 myocardial ischemia or myocardial infarction, arrhythmia (QTc ≥ 470ms), and ≥ grade 2 congestive heart failure

  4. History of interstitial lung disease, non infectious pneumonia, pulmonary fibrosis, or other uncontrolled acute lung diseases

  5. Active or uncontrolled severe infection (≥ CTCAE level 2 infection)

  6. Cirrhosis and active hepatitis; Active hepatitis (hepatitis B reference: HBsAg is positive, and the HBV DNA detection value exceeds the upper limit of normal value; Hepatitis C reference: HCV antibody positive and HCV virus titer detection value exceeding the upper limit of normal); Note: Subjects with positive hepatitis B B surface antigen or core antibody and patients with hepatitis C who meet the inclusion conditions need continuous antiviral treatment to prevent virus activation

  7. Active syphilis patients

  8. Renal failure requiring hemodialysis or peritoneal dialysis

  9. History of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases, or organ transplantation 7. Poor control of diabetes (fasting blood glucose [FBG]>10mmol/L) 8. Significant surgical treatment, open biopsy, or significant traumatic injury within 60 days prior to the start of treatment; Or long-term untreated wounds or fractures 9. Serious arterial/venous thrombotic events such as cerebrovascular accidents (including temporary ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism occurred within 6 months before the start of treatment 10. History of abuse of psychotropic drugs who are unable to quit or have mental disorders 11. History of severe allergies 12. Pregnant or lactating women

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intestinal microbiota transplantation combined with chemoradiotherapy and Sintilimab	Sintilimab plus Chemotherapy	Intestinal microbiota transplantation combined with synchronous radiotherapy, chemotherapy, and Sintilimab as neoadjuvant therapy
Intestinal microbiota transplantation combined with chemoradiotherapy and Sintilimab	Intestinal microbiota capsules	Intestinal microbiota transplantation combined with synchronous radiotherapy, chemotherapy, and Sintilimab as neoadjuvant therapy
Intestinal microbiota transplantation combined with chemoradiotherapy and Sintilimab	Standard Long Course Radiotherapy	Intestinal microbiota transplantation combined with synchronous radiotherapy, chemotherapy, and Sintilimab as neoadjuvant therapy
Intestinal microbiota transplantation combined with chemoradiotherapy and Sintilimab	Total mesorectal excision	Intestinal microbiota transplantation combined with synchronous radiotherapy, chemotherapy, and Sintilimab as neoadjuvant therapy

Primary Outcome Measures

Name	Time	Method
Event free survival rate	Three years after the end of treatment	The percentage of subjects who were followed up for 3 years and still survived without disease recurrence or change of treatment plan among all subjects.
Disease-free survival rate	Three years after the end of treatment	The percentage of subjects who were followed up for 3 years and still survived without disease recurrence among all subjects.
pathologic complete response rate	Up to 12 weeks	Defined as the percentage of subjects with ypT0N0 who have no residual tumor cells in the primary tumor and lymph nodes after surgery compared to all subjects.
Overall Survival	Three years after the end of treatment	The percentage of subjects who are still alive after 3 years of follow-up among all subjects.
R0 resection rate	During the surgery	Defined as the complete resection rate of tumors with negative margins removed under a microscope
Tumor regression grading	During the surgery	According to AJCC 8th edition, the Tumor regression grading is based on the proportion of fibrosis and residual tumors in the tumor. Grade 0 indicates complete regression of the tumor, Grade 1 indicates regression of over 90%, Grade 2 indicates regression between 10% and 90%, Grade 3 indicates regression of less than 10%, and Grade 4 indicates no significant regression of the tumor
Completion rate of neoadjuvant therapy	Up to 6 weeks	Defined as the percentage of subjects who have completed all neoadjuvant therapies compared to all subjects

Trial Locations

Locations (1)

First Affiliated Hospital of Ningbo University; 🇨🇳 Ningbo, Zhejiang, China