FMT Combined With Standard First-Line Therapy in Initially Unresectable Colorectal Cancer

Efficacy and Safety of Fecal Microbiota Transplantation Combined With First-Line Standard Therapy in Patients With Initially Unresectable Colorectal Cancer: A Multicenter, Open-Label, Randomized Controlled Trial

This clinical trial evaluates the efficacy and safety of adding fecal microbiota transplantation (FMT) to first-line standard of care for patients with initially unresectable colorectal cancer (CRC).

FMT is an established procedure designed to restore intestinal microbiome homeostasis by transferring processed fecal microbiota from a rigorously screened healthy donor into the patient's gastrointestinal tract. The standard first-line treatment regimen typically consists of chemotherapy, with or without targeted therapy.

Approximately 220 patients across 13 participating centers will be randomly assigned to receive either standard therapy alone or standard therapy combined with FMT. The primary endpoint is the objective response rate (ORR). Secondary endpoints include the conversion to resectability rate, progression-free survival (PFS), safety and adverse events, quality of life (QoL), anxiety and depression scales, as well as dynamic changes in the gut microbiome and circulating biomarkers.

The ultimate goal of this trial is to determine whether microbiome modulation via FMT can synergistically enhance the antitumor efficacy of standard first-line therapies and mitigate treatment-related toxicities in this patient population.

Inclusion Criteria:

• (1) Subjects must volunteer to participate in this study, sign the informed consent form (ICF), and demonstrate good compliance.

  (2) Patients aged 18 to 75 years (inclusive). (3) Meet the defined criteria for initially unresectable advanced metastatic colorectal cancer (mCRC) for this project.

  (4) Have not received first-line standard therapy. (5) Prior radiotherapy is permitted, provided it was completed more than 4 weeks prior to enrollment.

  (6) ECOG performance status of 0 to 1. (7) Life expectancy of ≥ 24 weeks. (8) Adequate major organ function meeting the following criteria (without the use of any blood components or cell growth factors within 2 weeks prior to enrollment): (9) Bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, white blood cell (WBC) count ≥ 4.0 × 10^9/L, platelets ≥ 100 × 10^9/L, hemoglobin ≥ 90 g/L.

  (10) Hepatic function: Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); if total bilirubin > 1.5 × ULN, direct bilirubin must be ≤ ULN. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (allowed up to 5 × ULN for patients with liver metastases).

  (11) Renal function: Blood urea nitrogen (BUN) and creatinine (Cr) ≤ 1.5 × ULN (and creatinine clearance rate (CCr) ≥ 50 mL/min).

  (12) Cardiac function: Normal cardiac function with a left ventricular ejection fraction (LVEF) ≥ 50%.

  (13) Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

  (14) Male or female patients of childbearing potential must volunteer to use effective contraceptive methods (e.g., double-barrier methods, condoms, oral or injectable contraceptives, intrauterine devices) during the study and for 6 months after the last dose of study medication. All female patients are considered to be of childbearing potential unless they are naturally postmenopausal, artificially postmenopausal, or surgically sterilized (e.g., hysterectomy, bilateral oophorectomy, or pelvic irradiation). Otherwise, female patients must have a negative serum pregnancy test (within 7 days prior to study enrollment) and must not be lactating.

Exclusion Criteria:

• (1) Presence of symptoms such as bleeding, perforation, or obstruction at the primary tumor site.

  (2) Presence of secondary intracranial tumors (brain metastases). (3) History of severe autoimmune diseases: active inflammatory bowel disease (including Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g., Wegener's granulomatosis), etc.

  (4) Symptomatic interstitial lung disease, or active infectious/non-infectious pneumonitis.

  (5) Risk factors for intestinal perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or other known risk factors for intestinal perforation.

  (6) Patients who have undergone other surgeries must wait for complete wound healing before being considered for enrollment.

  (7) History of other malignancies; except for cured localized tumors, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, and carcinoma in situ of the prostate, cervix, or breast, which are permitted for enrollment.

  (8) Patients planning to undergo or who have previously undergone organ transplantation or allogeneic bone marrow transplantation.

  (9) Moderate to severe ascites with clinical symptoms requiring therapeutic paracentesis or drainage, or a Child-Pugh score > 2 (excluding cases with only a small amount of ascites shown on imaging without clinical symptoms); uncontrolled or moderate to large pleural or pericardial effusions.

  (10) History of gastrointestinal bleeding within 6 months prior to the start of study treatment or a clear tendency for gastrointestinal bleeding, such as esophageal/gastric varices with bleeding risk or severe varices, localized active gastrointestinal ulcer lesions, or persistently positive fecal occult blood (if fecal occult blood is positive at baseline, it can be retested; if still positive, an esophagogastroduodenoscopy (EGD) is required. If EGD indicates esophageal/gastric varices with a risk of bleeding, the patient cannot be enrolled).

  (11) Occurrence of an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to the start of study treatment.

  (12) Patients who presented with signs/symptoms of incomplete obstruction/obstructive syndrome/ileus at initial diagnosis may be enrolled if the symptoms have completely resolved following definitive (surgical) treatment.

  (13) Known hereditary or acquired bleeding disorders (e.g., coagulopathy) or thrombotic tendency, such as hemophilia; current or recent (within 10 days prior to study treatment) use of full-dose oral or injectable anticoagulants or thrombolytic agents for therapeutic purposes (prophylactic use of low-dose aspirin or low molecular weight heparin is allowed).

  (14) Current or recent (within 10 days prior to study treatment) use of aspirin (> 325 mg/day, maximum antiplatelet dose), dipyridamole, ticlopidine, clopidogrel (≥ 75 mg), or cilostazol.

  (15) Occurrence of thrombotic or embolic events within 6 months prior to the start of study treatment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), pulmonary embolism, etc.

  (16) Active infection, heart failure, myocardial infarction within 6 months, unstable angina, or unstable arrhythmias.

  (17) Lactating or pregnant women. (18) History of hepatic encephalopathy. (19) Use of immunosuppressants or systemic corticosteroids for immunosuppressive purposes (dose > 10 mg/day of prednisone or equivalent) within 14 days prior to the start of study treatment.

  (20) Known severe allergic reaction to any monoclonal antibodies or anti-angiogenic targeted drugs.

  (21) Any other factors that, in the judgment of the investigator, may affect the study results or lead to premature termination of the study, such as alcohol abuse, drug abuse, other severe diseases (including psychiatric disorders) requiring concomitant treatment, or severe laboratory abnormalities.