Biomarkers for Apatinib and Bevacizumab in Second-line Therapy for Colorectal Cancer(BABST-C)

Inclusion Criteria:

* Inoperable colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer confirmed by histology
* Age ≥18 years ≤ 70 years at the time of informed consent
* Eastern Cooperative Oncology Group（ECOG）performance status (PS) ≤ 1
* Provided informed consent before study-specific screening procedures
* Life expectancy not less than 90 days
* Participants have progressive disease on or within 6 months post the combination of bevacizumab and 5-FU/leucovorin+oxaliplatin(FOLFOX) or capecitabine+oxaliplatin(CAPOX) as the first-line chemotherapy for metastatic colorectal cancer
* Adequate organ function based on the following laboratory values obtained within 14 days prior to enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test) Neutrophil count: ≥1500/mm3 Platelet count: ≥10.0 x 104/ mm3 Hemoglobin: ≥9.0 g/dL Total bilirubin: ≤1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT): ≤100 IU/L (≤200 IU/I if liver metastases present) Serum creatinine: ≤1.5 mg/dL Measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
* Adequate blood coagulation function \[International Normalized Ratio (INR) ≤1.5 and Partial Thromboplastin Time (PTT) or activated PTT (aPTT) ≤1.5 x upper limit of normal (ULN)). Participants on full-dose anticoagulation must be in a stable phase of anticoagulant therapy and if taking oral anticoagulation, participants must have an INR ≤3 without clinically significant active bleeding or a high risk of bleeding
* A historical colorectal cancer tissue sample is available for assessment of biomarkers with signed consent
* Signed informed consent to be provided

Exclusion Criteria:

* History of other malignancy with a disease-free survival \<5 years (excluding curatively treated cutaneous basal cell carcinoma, curatively treated cervical in situ carcinoma , and gastroenterological carcinoma confirmed to be cured by endoscopic mucosal resection)
* With a large amount of pleural effusions or ascites requiring intervention
* Radiological evidence of brain metastases or brain tumor
* Actively infectious condition including hepatitis
* One of the following complications: 1) Gastrointestinal obstruction (including paralytic ileus) or gastrointestinal bleeding 2) Symptomatic cardiac disease (including unstable angina, myocardial infarction, and heart failure) 3) Pulmonary fibrosis or interstitial pneumonia 4) Uncontrolled diarrhea (that affects daily activities although adequate therapy 5) Uncontrolled diabetes mellitus
* One of the following medical histories: 1) Myocardial infarction: One episode within one year prior to enrollment or two or more lifetime episodes 2) Remarkable hypersensitivity to any of the study drugs ii) History of side effect to fluoropyrimidines suggestive of dihydropyrimidine dehydrogenase (DPD) deficiency
* Pregnant or lactating females, and males and females reluctant to use contraception
* Psychiatric disability that would disturb study compliance
* Other conditions determined by the investigator to be not suitable for participation in the study
* History of concurrent gastrointestinal perforation or gastrointestinal perforation within 1 year prior to enrollment
* Pulmonary hemorrhage/hemoptysis ≥ Grade 2 (identified as bright red blood of not less 2.5mL) within 1 month before enrollment.
* History of thoracotomy,laparotomy, or intestinal resection within 28 day prior to enrollment
* Unhealed wound (other than suture wounds due to implantation of a central venous port), traumatic fracture, or gastrointestinal ulcer
* Current cerebrovascular disease or thromboembolism or either within 1 year before enrollment
* Current anticoagulation therapy or requiring anticoagulation agents (\> 325 mg/day of aspirin)
* Bleeding diathesis, coagulopathy, or coagulation factor abnormality (INR

  ≥1.5 within 14 days before enrollment)- Page 6 of 7 \[DRAFT\] -
* Uncontrolled hypertension Urine dipstick for proteinuria \>+2