1. Determine the maximum tolerable dose (MTD) and / or phase II recommended dose (RP2D) of the allotinib combined mXELIRI protocol.
2. To evaluate the safety and tolerance of the combination of anlotinib and mXELIRI in the second-line treatment of patients with advanced colorectal cancer

This study consists of two phases, the dose-escalation phase, and the expansion phase. 9-12 patients with advanced colorectal cancer will be included in the dose escalation study. Patients who met the inclusion criteria would be treated with anlotinib QD for 2 weeks, and then stopped for 1 week, combined with mXELIRI. Every 21 days was a treatment cycle. Safety information was collected until the disease progression or intolerable toxicity, so as to determine the MTD and / or RP2D of anlotinib combined with irinotecan in patients with advanced colorectal cancer. The study adopted the traditional 3+3 design .

The primary outcome in dose-expansion phase was objective response rate(ORR).

Inclusion Criteria:

• ECOG performance status (PS) 0-1
• The expected survival time is not less than 12 weeks
• Patients with stage IV colorectal cancer confirmed by pathology or imaging have measurable lesions (according to RECIST 1.1, the long diameter of tumor lesions on CT scan is greater than or equal to 10 mm, the short diameter of lymph node lesions on CT scan is greater than or equal to 15 mm, and the measurable lesions have not received radiotherapy, freezing and other local treatment);
• First line patients with advanced or intolerant colorectal cancer treated with bevacizumab combined with oxaliplatin (FOLFOX or capeox, etc.);
• The function of main organs was normal (in accordance with the chemotherapy standard);
• Women of childbearing age must have taken reliable contraceptive measures or conducted pregnancy test (serum or urine) within 7 days before enrollment, and the result is negative, and they are willing to use appropriate contraceptive methods during the test period and 8 weeks after the last administration of the test drug. For men, it is necessary to agree to use appropriate contraceptive methods or surgical sterilization during the trial period and 8 weeks after the last administration of the trial drug;
• The subjects volunteered to join the study and signed informed consent, with good compliance and follow-up.

Exclusion Criteria:

• The histological type was mucinous adenocarcinoma or ovarian implant metastasis;
• First line patients with irinotecan treatment;
• Patients who had been treated with anlotinib hydrochloride capsules in the past;
• Symptomatic brain metastases (patients with stable symptoms and completed treatment 21 days before enrollment can be enrolled, but no cerebral hemorrhage symptoms should be confirmed by brain MRI, CT or venography evaluation);
• Patients with hypertension who could not be well controlled by single antihypertensive drug treatment (systolic blood pressure ≥ 150 mmHg, diastolic blood pressure ≥ 100 mmHg); Or use two or more antihypertensive drugs to control blood pressure
• The patient also had more than 1 degree of adverse reactions (except hair loss, neurotoxicity more than 2 degrees) which could not be alleviated due to previous treatment;
• They have the following cardiovascular diseases: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including QTc interval ≥ 450 ms for male and ≥ 470 MS for female); According to NYHA criteria, grade Ⅲ - Ⅳ cardiac insufficiency, or left ventricular ejection fraction (LVEF) < 50% by echocardiography;
• Abnormal coagulation function (INR > 1.5 or PT > ULN + 4 seconds or APTT > 1.5 ULN), bleeding tendency or receiving thrombolysis or anticoagulation therapy;
• There were significant clinical bleeding symptoms or clear bleeding tendency in the first 3 months, such as gastrointestinal bleeding, hemorrhagic hemorrhoids, hemorrhagic gastric ulcer, baseline fecal occult blood + + or above, or vasculitis;
• Arteriovenous thrombotic events occurred in the first 12 months, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep venous thrombosis and pulmonary embolism;
• Known hereditary or acquired bleeding and thrombotic tendency (such as hemophilia, coagulation dysfunction, thrombocytopenia, hypersplenism, etc.);
• Wound or fracture that has not been cured for a long time (pathological fracture caused by tumor is not included);
• Patients in the study group had undergone major surgery or severe traumatic injury, fracture or ulcer within 4 weeks;
• There are obvious factors affecting oral drug absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction;
• Abdominal fistula, gastrointestinal perforation or abdominal abscess occurred within 6 months before admission;
• Urine routine showed that urine protein was ≥ + +, and 24-hour urine protein was more than or equal to 1.0 G;
• Serous effusion (including pleural effusion, ascites and pericardial effusion) with clinical symptoms and requiring symptomatic treatment;
• Asymptomatic serous effusion can be included in the group, symptomatic serous effusion after active symptomatic treatment (can not use anticancer drugs for serous effusion treatment), patients who can be included in the group after the judgment of the researchers are allowed to be included in the group.
• Active infections need antimicrobial treatment (for example, the use of antibiotics and antiviral drugs, excluding chronic hepatitis B anti hepatitis B treatment, antifungal treatment).
• There was active hepatitis B (HBV DNA > 2000IU/mL or 104 copy number /mL) or hepatitis C (hepatitis B antibody positive, and HCV RNA was higher than the lower limit of analysis).
• Those who have a history of psychotropic drug abuse and can not give up or have mental disorders;
• Those who participated in clinical trials of other anti-tumor drugs within 4 weeks before enrollment;
• Previous or other untreated malignancies were cured except for basal cell carcinoma, cervical carcinoma in situ and superficial bladder cancer.
• Those who received strong CYP3A4 inhibitor treatment within 7 days before randomization, or those who received strong CYP3A4 inducer treatment within 12 days before participating in the study;
• Pregnant or lactating women; Patients with fertility are unwilling or unable to take effective contraceptive measures;
• The researcher judges other situations that may affect the clinical research and the judgment of research results.