Fruquintinib Plus Capecitabine Versus Bevacizumab Plus Capecitabine as Maintenance Therapy Following First-line Treatment for Metastatic Colorectal Cancer

A Phase II, Randomized, Controlled Study to Assess the Efficacy and Safety of Fruquintinib Plus Capecitabine Versus Bevacizumab Plus Capecitabine as Maintenance Treatment Following First-line Chemotherapy for Metastatic Colorectal Cancer

This is an open-label, multicenter, randomized phase 2 study evaluating the efficacy and safety of fruquintinib plus capecitabine versus bevacizumab plus capecitabine as maintenance therapy following first-line treatment for metastatic colorectal cancer. Patients who have already achieved disease control (including CR/PR and SD), without discontinuation for toxicity, and are progression free after 4-6 months of standard first-line induction treatment will be assigned to 2 maintenance treatment groups by randomization in a 1:1 ratio to receive fruquintinib + capecitabine (Arm A) or bevacizumab + capecitabine (Arm B). The study contains a safety lead-in phase in which the safety and tolerability of fruquintinib + capecitabine will be assessed prior to the phase 2 portion of the study. All patients from Arm A and Arm B will be treated until progressive disease, death from any cause, unacceptable toxicity or informed consent withdrawal (whichever occurs earlier).

Inclusion Criteria:

1. 18-75 years old (including 18 and 75) at the time of signing the informed consent;

2. Patients who have been histologically or cytologically confirmed adenocarcinoma of the colon or rectum (stage IV);

3. Patients who have achieved disease control (including CR/PR and SD) after 4-6 months of first-line standard chemotherapy (FOLFOX, FOLFIRI, XELOX ± targeted therapy) and are progression free at the start of maintenance therapy;

4. At least one measurable metastatic lesion(s) as defined by RECIST version 1.1;

5. ECOG performance status of 0-1;

6. Body weight ≥40Kg;

7. LVEF≥50%;

8. Life expectancy≥3 months;

9. Adequate organ and bone marrow functions:

   Neutrophils >1.5×109/L, platelets >100×109/L, and hemoglobin >9 g/dL; Total bilirubin <1.5×upper limit of normal (ULN); aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) <2.5×ULN (<5×ULN in case of liver metastases); Creatinine clearance (calculated according to Cockcroft and Gault) ≥50 mL/min; Urinary protein / creatinine ratio < 1 (or urine analysis < 1 + or 24-hour urinary protein < 1g / 24 h);

10. Able to take oral medication;

11. Women of childbearing age must have a negative pregnancy test within the first day of the study, and contraceptive methods should be taken during the study until 6 months after the last administration;

12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedure.

Exclusion Criteria:

1. Pregnant or lactating women;
2. Any factors that influence the usage of oral administration;
3. Those who have been proved to be allergic to fruquintinib and / or its excipients;
4. Blood transfusion was performed within 1 week before randomization;
5. Non-controlled hypertension after monotherapy, that is, systolic blood pressure > 140mmHg or diastolic blood pressure > 90mmHg;
6. Intercurrence with one of the following: coronary artery disease, arrhythmia and heart failure;
7. Clinically significant electrolyte abnormality;
8. Proteinuria ≥ 2+ (1.0g/24hr);
9. Previous treatment with VEGFR inhibition;
10. Evidence of CNS metastasis;
11. Severe intolerance to capecitabine or 5-FU;
12. Disability of serious uncontrolled intercurrence infection;
13. Uncontrolled hemorrhage in GI;
14. Have evidence or a history of bleeding tendency within two months of the enrollment;
15. Abdominal fistula or gastrointestinal perforation occurred within 6 months before the first treatment, unless repaired by surgery;
16. Within 12 months before the first treatment occurs artery/venous thromboembolic events, such as cerebral vascular accident (including stroke and transient ischemic attack) , etc.;
17. Within 6 months before the first recruitment occurs acute myocardial infarction, acute coronary syndrome or CABG;
18. Incomplete healing of skin trauma, surgical site, wound site or severe mucosal ulcer. Bone fracture or wounds that was not cured for a long time;
19. APTT and /or PT >1.5×ULN;
20. Clinically detectable secondary primary malignancies at the time of enrollment, or had other malignancies in the past 5 years (excluding fully treated basal cell carcinoma of the skin or carcinoma in situ of the cervix);
21. Patients who are not suitable for the study judged by the researchers.