FMT Combined With Immune Checkpoint Inhibitor and TKI in the Treatment of CRC Patients With Advanced Stage

Phase II, Single-arm Study of FMT Combined With Immune Checkpoint Inhibitor and TKI in the Treatment of Colorectal Cancer Patients With Advanced Stage

A single-arm, phase II study was designed to evaluate the efficacy and safety of fecal microbiota transplantation plus Sintilimab and Fruquintinib as the later line treatment in colorectal patients with advanced stages.

The combination of regorafenib plus nivolumab had already presented a manageable safety profile and encouraging antitumor activity in patients with mCRC as the REGONIVO trail reported. While additional investigations showed limited ORRs between 7%-33% as third or later line treatement in mCRC. Gut microbiota modulation, with the aim to reverse established microbial dysbiosis, is a novel strategy for the treatment of CRC. The individualized gut microbiome transplantation may further imrpove the efficacy of the combination therapy of CPI and TKI. Thus, a single-arm, phase II study was designed to evaluate the efficacy and safety of FMT plus Sintilimab and Fruquintinib as the later line treatment in CRC patients with advanced stages.

Inclusion Criteria:

• Sign the informed consent form.
• Metastatic or locally advanced colorectal adenocarcinoma unresectable or unfit for radical radiochemotherapy confirmed by pathology or cytology.
• Microsatellite stable or pMMR patients failed standard treatment, including platinum, irinotecan, fluorouracil and Bevacizumab (Ras and BRAF wt patients should recived Cetuximab).
• Patients have at least one lesion could be evaluated by RECIST v1.1 or mRECIST.
• The Eastern Cooperative Oncology Group (ECOG) performance status score was 0 or 1.
• The life expectancy is more than 3 months.
• Good organ function:

Blood routine: hemoglobin ≥90g/L, white blood cell ≥3.0×10^9/L, neutrophil ≥1.5×10^9/L, platelet ≥100×10^9/L; Renal function: creatinine≤1.5×upper limit of normal (UNL) or creatinine clearance ≥60ml/min; Liver function: total bilirubin (TBIL)≤1.5×upper limit of normal (UNL); ALT≤2.5×UNL, AST≤2.5×UNL, ALT≤5×UNL and AST≤5×UNL for patients with liver metastasis.

Exclusion Criteria:

• Have received any anti-PD-1, anti-PD-L1/L2 antibodies, anti-CTLA-4 antibodies and other immunotherapy in the past.
• Have received any TKI therapy in the past.
• Clinically significant ascites.
• Known to have allergic reactions to any ingredients or excipients of experimental drugs.
• Have received any antibiotics within 28 days before the first medication or any probiotics or prebiotics within 14 days before the first medication.
• Radiotherapy, RFA, interventional therapy or surgery were performed within 28 days before the first medication (except for previous diagnostic biopsy).
• Other active malignant tumors, excluding those who have been disease free for more than 5 years or in situ cancer considered to have been cured by adequate treatment.
• Brain metastasis or meningeal metastasis has been confirmed. Patients with neurological symptoms should receive brain CT / MRI examination to exclude metastasis.
• Patients who is suffering from intestinal obstruction, gastrointestinal bleeding, pulmonary fibrosis or interstitial pneumonia, renal failure, liver failure or cerebrovascular disease.
• Diabetes was not controlled, defined as HbA1c > 7.5% after anti-diabetic drugs or hypertension was not controlled, defined as systolic / diastolic blood pressure > 140 / 90 mmHg after antihypertensive drug.
• Myocardial infarction, severe/unstable angina, New York Heart Association (NYHA) class III or IV congestive heart failure in the past 12 months.
• Known to be infected with human immunodeficiency virus (HIV), have acquired immunodeficiency syndrome (AIDS) related diseases, have active hepatitis B or hepatitis C.
• Suffering from autoimmune diseases or history of organ transplantation requiring immunosuppressive therapy.
• May increase the risk associated with participation in the study or administration of the study drug or mental illness that may interfere with the interpretation of research results.
• Pregnant women (determined by serum human chorionic gonadotropin [hCG]) or lactating women, or plan to conceive during the treatment period, 2 months after cetuximab treatment and 6 months after capecitabine treatment. Women of childbearing age with positive or no pregnancy test at baseline. Women of childbearing age or sexually active men were not willing to use contraception during the study period, at least 2 months after cetuximab treatment and 6 months after capecitabine treatment. Postmenopausal women must be amenorrhea for at least 12 months to be considered infertile.
• There are other serious diseases that the researchers believe patients cannot be included in the study