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.

Study Overview

• Status: Not yet recruiting
• Conditions: Unresectable Colorectal Cancer; Colorectal Cancer (Locally Advanced or Metastatic)
• Intervention / Treatment: Drug: Standard First-Line Therapy; Combination product: FMT Combined with Standard First-Line Therapy

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Qiyi Chen; Phone Number: +86 15896453859; Email: qiyichen2011@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard First-Line Therapy; Patients receive investigator's choice of standard first-line systemic therapy for initially unresectable colorectal cancer (e.g., chemotherapy ± targeted therapy or anti-angiogenic agents according to CSCO/NCCN guidelines and RAS status).	Drug: Standard First-Line Therapy; Investigator's choice of standard first-line systemic therapy for initially unresectable colorectal cancer, including chemotherapy (e.g., FOLFOX, FOLFIRI, CAPOX) with or without targeted therapy or anti-angiogenic agents (e.g., cetuximab, panitumumab for RAS wild-type; bevacizumab for others), according to CSCO/NCCN guidelines and RAS mutation status.
Experimental: FMT Combined with Standard First-Line Therapy; Patients receive fecal microbiota transplantation (FMT) in addition to the same standard first-line systemic therapy as in the control arm. FMT is administered according to the study protocol (donor-screened, prepared under GMP/P2 conditions, capsule delivery).	Drug: Standard First-Line Therapy; Investigator's choice of standard first-line systemic therapy for initially unresectable colorectal cancer, including chemotherapy (e.g., FOLFOX, FOLFIRI, CAPOX) with or without targeted therapy or anti-angiogenic agents (e.g., cetuximab, panitumumab for RAS wild-type; bevacizumab for others), according to CSCO/NCCN guidelines and RAS mutation status.; Combination product: FMT Combined with Standard First-Line Therapy; Fecal microbiota transplantation using donor stool from healthy screened donors. Prepared under P2/GMP conditions as capsules or suspension. Administered in addition to standard therapy per study protocol (induction phase followed by maintenance).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective Response Rate	Up to 12 months (from randomization to best overall response assessment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conversion Resection Rate (R0)	Proportion of participants who achieve R0 resection (microscopically negative margins) after conversion therapy, confirmed by pathology. Assessed by multidisciplinary team (MDT) discussion.	Up to 12 months
Progression-Free Survival (PFS)	Time from randomization to first documented disease progression (per RECIST 1.1 by BICR) or death from any cause, whichever occurs first.	Up to 12 months
Disease Control Rate	Percentage of participants achieving CR, PR, or stable disease (SD) as best overall response per RECIST 1.1 (BICR).	Up to 12 months
Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Incidence and severity of all AEs and SAEs graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Includes FMT-related infections and gastrointestinal events.	From first dose through 30 days after last dose (up to 12 months)
Relative Dose Intensity (RDI) of Standard Therapy	Proportion of planned dose of standard first-line therapy actually delivered (calculated as actual dose / planned dose × 100). Compares treatment compliance between arms.	Up to 12 months
Patient-Reported Outcomes (PROs) - Hospital Anxiety and Depression Scale (HADS)	Change from baseline in anxiety and depression scores assessed by HADS questionnaire.	Baseline, every 8 weeks during treatment, and end of treatment (up to 12 months)
Patient-Reported Outcomes (PROs) - EORTC QLQ-C30	Change from baseline in global health status, functional scales, and symptom scales (fatigue, nausea/vomiting, pain, etc.) assessed by EORTC QLQ-C30 questionnaire.	Baseline, every 8 weeks during treatment, and end of treatment (up to 12 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Serum Metabolites	Dynamic changes in core serum metabolites (tryptophan/kynurenine pathway, secondary bile acids, short-chain fatty acids, iron/heme-related metabolites) and their correlation with HADS scores and treatment toxicity.	up to 12 months
Changes in Gut Microbiome Composition	Alpha- and beta-diversity changes, abundance shifts in key taxa (Fusobacterium nucleatum, Bacteroides fragilis, Escherichia coli, Candida spp., etc.), and phage proportion changes assessed by metagenomic sequencing.	up to 12 months

Collaborators and Investigators

• Sponsor: Shanghai 10th People's Hospital
• Collaborators: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; The First Hospital of Jilin University; Southern Medical University, China; China-Japan Union Hospital, Jilin University; Guangdong Second Provincial General Hospital; Wuhan Central Hospital; The General Hospital of Eastern Theater Command; Maoming People's Hospital; Shanxi Bethune Hospital; PLA Rocket Force Characteristic Medical Center; Northern Jiangsu People's Hospital

Publications and helpful links

General Publications

• Duttagupta S, Messaoudene M, Hunter S, Desilets A, Jamal R, Mihalcioiu C, Belkaid W, Marcoux N, Fidelle M, Suissa D, Ponce M, Geiger M, Malo J, Piccinno G, Puncochar M, Filin A, Heidrich V, Rusu D, Mbaye B, Durand S, Ben Aissa I, Puller V, de Lahondes R, Blais N, Tehfe M, Owen S, Belanger K, Parvathy SN, Shieh B, Raphael J, Lenehan J, Breadner D, Rothenstein J, Rozza N, Maillou J, Nili S, Prifti DK, Pinto F, Armanini F, Kim-Schulze S, Marron TU, Kroemer G, Derosa L, Zitvogel L, Silverman M, Segata N, Maleki Vareki S, Routy B, Elkrief A. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nat Med. 2026 Jan 28. doi: 10.1038/s41591-025-04186-5. Online ahead of print.
• Fernandes R, Jabbarizadeh B, Rajeh A, Hong MMY, Baines KJ, Ernst S, Winquist E, Ali AS, Penny S, Figueredo R, Parvathy SN, Lenehan JG, Pinto DM, Silverman MS, Maleki Vareki S. Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial. Nat Med. 2026 Jan 28. doi: 10.1038/s41591-025-04183-8. Online ahead of print.
• Chen YC,Chuang CH,Miao ZF,Yip KL,Liu CJ,Li LH,Wu DC,Cheng TL,Lin CY,Wang JY
• Zhao W,Lei J,Ke S,Chen Y,Xiao J,Tang Z,Wang L,Ren Y,Alnaggar M,Qiu H,Shi W,Yin L,Chen Y
• Yang Y,An Y,Dong Y,Chu Q,Wei J,Wang B,Cao H
• Gu C,Sha G,Zeng B,Cao H,Cao Y,Tang D
• Kim Y, Kim G, Kim S, Cho B, Kim SY, Do EJ, Bae DJ, Kim S, Kweon MN, Song JS, Park SH, Hwang SW, Kim MN, Kim Y, Min K, Kim SH, Adams MD, Lee C, Park H, Park SR. Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. Cell Host Microbe. 2024 Aug 14;32(8):1380-1393.e9. doi: 10.1016/j.chom.2024.06.010. Epub 2024 Jul 25.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: March 29, 2026
• First Submitted That Met QC Criteria: March 29, 2026
• First Posted (Actual): April 3, 2026

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 29, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Colorectal Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: FMT-CRC-2026-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Yes. De-identified individual participant data (IPD) that underlie the primary and key secondary outcomes of this trial will be made available to qualified external researchers who provide a methodologically sound proposal. Proposals should be directed to the Principal Investigator. Data will be available beginning 12 months after publication of the primary study results and ending 5 years after publication. Access will require approval of a formal data sharing request and a signed data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No