Regorafenib and XELOX as 2nd Line Treatment in Metastatic Colorectal Cancer

Phase Ib/II Study of Regorafenib and XELOX Combination as 2nd Line Treatment in Metastatic Colorectal Cancer Patients

This is an interventional, randomized open-label, parallel-group, multicenter, dose escalation phase Ib/II study, to investigate the combination of Regorafenib and XELOX as 2nd line treatment in mCRC patients.

This is a phase Ib/II trial, comprising Phase Ib and Phase II two parts. Phase Ib study is an open-label, single-arm, multicenter, dose escalation study of Regorafenib plus XELOX. In Phase Ib, max 15 patients(pts) could be enrolled based on the modified toxicity probability interval (mTPI) design. Phase II study is a randomized, open-label, parallel-group, multicenter study comparing Regorafenib + XELOX to XELOX alone. In phase II trial, a total of 39 patients will be recruited and randomized 2:1 into two groups, where 26 patients under Regorafenib + XELOX, and 13 patients under XELOX alone.

Inclusion Criteria:

1. Sign a consent form
2. Age> 18 years <75 years
3. Pathological diagnosis as colorectal adenocarcinoma
4. Recurrence or metastatic disease
5. Metastatic colorectal cancer with disease progression after 1st line treatment by 5-Fu and Irinotecan
6. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
7. ECOG score 0-1 points
8. Life expectancy ≥3 months
9. Can provide more than 10 paraffin sections of tumor tissue
10. End of radiotherapy without or with non-targeted lesions> 4 weeks (only for use outside of the test site)
11. At least one measurable lesion (according to RECIST 1.1)
12. Previously treated radiotherapy lesions cannot be considered as target lesions, unless the radiotherapy lesions clear progress.
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤ 2.5 times the upper limit of normal (ULN), patients with liver metastases ≤ 5 times ULN
14. Serum albumin ≥ 3.0g / dL
15. Serum alkaline phosphatase (AKP) ≤2.5 times ULN
16. Total bilirubin <1.5mg / dL
17. Estimated creatinine clearance (CLcr) ≥ 30 mL/min as calculated using the Cockcroft-Gault equation
18. Lipase ≤ 1.5 x the ULN
19. Neutrophil absolute count (ANC) ≥ 1500 / mm3, hemoglobin (Hb)> 9g/dl, platelets> 100,000 / mm3
20. Pregnant or breast-feeding patients:

1) Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.

2) Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment

Exclusion Criteria:

1. Received oxaliplatin and capecitabine in the 1st line treatment
2. Cannot be orally administered
3. Subjects with brain metastases and / or cancerous meningitis.
4. Surgical treatment was performed within 4 weeks before enrollment (excluding diagnostic biopsies)
5. Non-healing wound, non-healing ulcer, or non-healing bone fracture
6. Patients with evidence or history of any bleeding diathesis, irrespective of severity
7. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication.
8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)
9. Congestive heart failure ≥ New York Heart Association (NYHA) class 2
10. Uncontrolled cardiac arrhythmias
11. Ongoing infection > Grade 2 NCI CTCAE
12. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
13. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
14. Anti-tumor cytotoxic drug therapy, biologic medication (eg, monoclonal antibody), immunotherapy (eg, interleukin 2 or interferon), or other investigational drug therapy within 4 weeks prior to enrollment
15. Subjects with active tuberculosis (TB) who are on anti-TB treatment or who have received anti-TB treatment within 1 year prior to screening
16. Patients with complications requiring long-term use of immunosuppressive drug therapy or systemic or topical corticosteroids requiring immunosuppressive doses (prednisone or other equivalent hormones at doses> 10 mg / day)
17. Use of strong CYP3A4 inducers or inhibitors
18. In the first 4 weeks before the group vaccinated any anti-infective vaccine (such as influenza vaccine, varicella vaccine, etc.)
19. Pregnancy or lactation
20. 5 years with other malignancies, except for non-melanoma skin cancer
21. Persistent proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (Grade 3, NCI-CTCAE v 5.0).
22. Human immunodeficiency virus (HIV) positive
23. Hepatitis B surface antigen (HBsAg) positive simultaneous detection of Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) copy number positive (quantitative detection ≥ 1000cps / ml)
24. Chronic hepatitis C blood screening positive [Hepatitis C virus (HCV) antibody positive]
25. No legal capacity
26. Any other disease or condition that the investigator considers may affect program adherence or affect the subject's signature of informed consent (ICF), or are not suitable for participating in this clinical trial.