Anlotinib Plus Penpulimab (AK105) for Chemo-refractory Metastatic Colorectal Cancer:ALTER-C003

Inclusion Criteria:

* Patients participate in the study voluntarily and sign informed consent with good compliance.
* Be 18 years of age or older on day of signing informed consent.
* Histological or cytological confirmation of Metastatic Colorectal Cancer(T1-4N0-2M1).
* At least one measurable lesion, with diameter ≥ 10mm measured by spiral MRI/CT scan per RECIST1.1.
* Participants must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, Exceptions may apply.
* Eastern Cooperative Oncology Group Performance Status 0 or 1.
* Life expectancy of at least 3 months.
* Main organs function is normal. (normal main organs function as defined below: Hemoglobin (Hb) ≥ 90 g/L, Neutrophils (ANC) ≥ 1.5×109/L, leucocyte (WBC) ≥ 3.0×109/L,Platelet count (PLT) ≥ 75×109/L,Total bilirubin (TBIL) ≤ 1.5 × normal upper limit (ULN), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 ×ULN, If liver metastasis is present，ALT and AST\<5ULN ；Serum creatinine (Cr) ≤ 1.5× ULN or Creatinine Clearance rate(CCr) ≥60ml/min，Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) \> 50%)
* The woman patients of childbearing age who must agree to take contraceptive methods (e.g. intrauterine device, contraceptive pill or condom) during the research and within another 3 months after it; who are not in the lactation period and examined as negative in blood serum test or urine pregnancy test within 7 days before the research; The man patients who must agree to take contraceptive methods during the research and within another 8 weeks after it.

Exclusion Criteria:

* Histological or cytological confirmation of mucinous adenocarcinoma or ovarian transcoelomic metastasis
* Patients who had previously received treatment with Anlotinib or anti-programmed cell death protein 1 (PD-1), programmed cell death protein 1 ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors other immunotherapy against .
* Patients who had previously received treatment within 2 weeks or Participated in other anti-tumor clinical trials within 4 weeks.
* Patients with a large amount of pleural effusion or ascites requiring drainage.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
* Patients who underwent major surgery within 4 weeks.
* Regardless of the severity, patients with any physical signs or history of bleeding, patients with bleeding or bleeding events greater than or equal to CTCAE 3 within four weeks prior to the first administration, or patients with unhealed wounds, fractures, ulcers.
* Patients with a risk of gastrointestinal bleeding may not be enrolled.
* Patients with arterial or venous thromboembolic events occurred within 6 months, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis and pulmonary embolism.
* Patients with any severe and/or unable to control diseases，including： Patients with unsatisfactory blood pressure control using antihypertensive drugs (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100) mmHg); Patients with Grade 2 or higher myocardial ischemia, myocardial infarction or malignant arrhythmias(including male QTc≥450ms; female QTc≥470ms) and patients with Grade 2 or higher congestive heart failure (NYHA Classification); Patients with active or unable to control serious infections, which is over level 2 in CTC AE (4.0); Patients with poorly controlled diabetes (fasting blood glucose(FBG)\>10mmol/L); Patients with kidney failure who require hemodialysis or peritoneal dialysis; Patients with interstitial lung disease with symptoms or signs of activity；Patients with a history of immunodeficiency, including a positive HIV test or other acquired, congenital immunodeficiency disease, or a history of organ transplantation; Urine routine indicates that urine protein ≥ ++, and confirmed 24-hour urine protein quantitation \> 1.0 g; Patients with any of the following coagulation functions are abnormal, including: Prothrombin time (PT)\>ULN+4s, Activated partial thromboplastin time (APTT) \>1.5ULN s, international normalized ratio (INR)\>1.5; Patients with a seizure disorder who require pharmacotherapy.
* Patients who have got non remissive toxic reactions derived from any treatment, which is over level 1 in CTC AE (4.0).
* Has a diagnosis of immunodeficiency or is receiving chronic steroid therapy of prednisone ≥ 10 mg daily or any equivalent dose of corticosteroids.
* Has received a live vaccine or attenuated vaccine within 30 days prior to trial registration.
* Symptoms that affect oral medication and cannot be controlled through proper treatment (such as inability to swallow, chronic diarrhoea and intestinal obstruction, etc.).
* Female patients who are pregnant or breastfeeding.
* Patients with drug abuse history and unable to get rid of or patients with mental disorders.
* Patients who had serious adverse effect to Anlotinib or Penpulimab or any of its excipients
* Known hypersensitivity to other Monoclonal Antibody or any of its excipients.
* Patients with concomitant diseases which could seriously endanger their own safety or could affect completion of the study according to investigators' judgment.