Fruquintinib Plus Camrelizumab and HAIC in the Treatment of Non-MSI-H Advanced Colorectal Cancer

Inclusion Criteria:

• The subjects volunteered to join the study and signed informed consent, with goodcompliance and follow-up.

• Patients with histologically or cytologically confirmed non-MSI-H ( according to thedetection criteria of the institutional testing center, immunohistochemistry, PCR orNGS detection can be used ) unresectable advanced colorectal cancer with livermetastasis ;

• Age ≥ 18 years, ≤75 years， male or female ;

• ECOG PS 0-1;

• Expected overall survival ≥3 months

• Patients must have at least one measurable liver metastases (RECIST 1.1)

• Patients who had only received one standard first-line systemic treatment and wereconfirmed to be ineffective, or could not tolerate first-line treatment ;

• Patients must have adequate organ and bone marrow function( No blood components andcell growth factors were used within 14 days before enrollment )

• Male or female patients with fertility voluntarily used effective contraceptivemethods, such as double-barrier contraceptive methods, condoms, oral or injectablecontraceptives, intrauterine devices, etc., during the study period and within 6months of treatment in the last study. All female patients will be considered tohave fertility, unless the female patient has natural menopause, artificialmenopause or sterilization ( such as hysterectomy, bilateral adnexectomy orradioactive ovarian irradiation, etc. ), otherwise the female patient 's serum orurine test showed no pregnancy within 7 days before the study, and must benon-lactating patients.

Exclusion Criteria:

• Patients who are allergic or suspected to be allergic to the study drug or similardrugs

• Patients had other malignant tumors in the past 5 years or at the same time (exceptfor the cured skin basal cell carcinoma and cervical carcinoma in situ);

• Participating in other clinical trials and received at least one treatment within 4weeks before enrollment

• Patients with autoimmune disease or history of autoimmune disease within 4 weeksbefore enrollment

• patients currently have central nervous system (CNS) metastasis or previous brainmetastasis and the symptom control time is less than 2 months

• Patients cannot take fruquintinib orally

• Patients who have received organ transplantation and bone marrow transplantation inthe past

• Have taken other strong inducers or inhibitors of CYP3A4, P-gp substrates and BCRPsubstrates within 2 weeks before the First medication

• Received any operation (except biopsy) or invasive treatment or operation (exceptvenous catheterization, puncture and drainage, etc.) within 4 weeks beforeenrollment

• Pleural effusion or ascites causing relevant clinical symptoms, includingrespiratory syndrome (dyspnea≥CTC AE grade 2)

• Clinically significant electrolyte abnormality#

• Systolic blood pressure > 140mmHg or diastolic blood pressure > 90mmHg regardless ofany antihypertensive drugs; Or patients need more than two antihypertensive drugs

• Proteinuria ≥ 2+ (1.0g/24hr);

• Active gastric and duodenal ulcer, ulcerative colitis or uncontrolled hemorrhage inGI, or other conditions that may cause GI bleeding and perforation as determined bythe investigator;

• Have evidence or history of bleeding tendency within 3 months or thromboembolicevents within 12 months before enrollment( Hemorrhage > 30 mL within 3 months,hematemesis, black feces, hematochezia ), hemoptysis ( fresh blood > 5 mL within 4weeks ) or thromboembolic events ( including stroke events and / or transientischemic attack ) within 12 months ;

• Clinically significant cardiovascular disease, including but not limited to acutemyocardial infarction, severe/unstable angina pectoris or coronary artery bypassgrafting within 6 months before enrollment; NYHA classification > 2 Grade;ventricular arrhythmia requiring medical therapy; ECG showing QTc interval ≥ 480 ms

• Active or uncontrolled serious infection (≥CTCAE grade 2 infection)

• Pregnant or lactating women

• Any other disease, with clinically significant metabolic abnormalities, physicalexamination abnormalities or laboratory abnormalities, according to the judgment ofinvestigator that the patient is not suitable for the the study drug (such as havingepileptic seizures and require treatment), or would affect the interpretation ofstudy results, or put patients at high risk

• Clinical uncontrolled active infections, including human immunodeficiency virus (HIV) infection, active hepatitis B / C (HBV DNA Positive[1×104 copies/mL or >2000IU/ml], HCV RNA positive[>1×103 copies/mL]);

• Patients have other factors that may affect the results of the study or cause thestudy to be terminated halfway, such as alcoholism, drug abuse, other seriousdiseases (including mental diseases) that require concomitant treatment, and seriouslaboratory abnormalities. Accompanied by family or social factors, which will affectthe safety of patients.