CMAB009 Combined With FOLFIRI First-line Treatment in Patients With RAS/BRAF Wild-type, Metastatic Colorectal Cancer

Open, Randomized, Controlled, Multicenter Phase III Study Comparing CMAB009 Plus FOLFIRI Versus FOLFIRI Alone as First-line Treatment for Epidermal Growth Factor Receptor-expressing, RAS/BRAF Wild-type, Metastatic Colorectal Cancer

Drugs used against cancer work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as CMAB009, can block tumor growth in different ways. Giving combination chemotherapy together with CMAB009 as first treatment after diagnosis of a metastatic colorectal cancer（first-line treatment）may improve the treatment efficacy. However, it is not yet known whether giving combination chemotherapy together with CMAB009 is more effective than combination chemotherapy alone. This open-label trial investigates the effectiveness of CMAB009 in combination with a standard and effective chemotherapy FOLFIRI（5-Fluorouracil /Folinic acid plus Irinotecan）for RAS/BRAF wild-type, metastatic colorectal cancer in first-line setting, compared to the same chemotherapy alone.

Patients will be randomly assign in one of the two groups to either receive the combination chemotherapy alone or with CMAB009 and will then be treated until progression of the disease or unacceptable toxicity occurred. Regular efficacy assessments（every 8 weeks）based on imaging will be performed throughout the study together with regular safety assessments.

After participant discontinuation from the trial, regular updates on further treatments and survival status will be requested from the investigator.

Inclusion Criteria:

1. Males or females, Aged ≥18 years and ≤75 years
2. Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum
3. First occurrence of metastatic disease(not curatively resected)
4. RAS/BRAF wild-type status in tumor tissue
5. At least one measurable lesion by computer tomography(CT) or magnetic resonance imaging (MRI)according to RECIST1.1 criteria (not in an irradiated area)
6. Eastern Cooperative Oncology Group(ECOG)performance status of 0 or 1 at trial entry
7. Life expectancy of at least 3 months
8. Medically accepted effective contraception if procreative potential exists(applicable for both male and female subjects until at least 90 days after the last dose of trial treatment)
9. Recovery from relevant toxicity due to previous treatment before trial entry
10. Signed the informed consent form voluntarily

Exclusion Criteria:

1. Radiotherapy or surgery（excluding prior diagnostic biopsy）in the 30 days before trial treatment

2. Hepatic, marrow, liver and renal function as follows:

   Marrow: white blood cell count <3.0 × 109/L with neutrophils<1.5 × 109/L, platelet count<100×109/L and hemoglobin<90 g/L; Liver function: Total bilirubin >1.5 × upper limit of reference range; Aspartate transaminase (AST) and alanine transaminase (ALT) > 2.5 × upper limit of reference range , or> 5 × upper reference range in subjects with liver metastasis; Renal function: Serum creatinine >1.5 × upper limit of reference range, or creatinine clearance<50 mL/min

3. Previous chemotherapy for CRC adjuvant treatment if terminated <12 months before diagnosis of recurrence or metastatic disease

4. Previous treatment with anti-EGFR monoclonal antibody, epidermal growth factor receptor tyrosine kinase inhibitor, or other EGFR targeted inhibitors(such as cetuximab, Nimotuzumab, or panitumumab)

5. Known hypersensitivity or allergic reactions against any of the components of the trial treatments

6. History of organ allograft, autologous stem cell transplantation, or allogeneic stem cell transplantation

7. Other non-permitted concomitant anti-cancer therapies

8. Known brain metastasis and/or leptomeningeal disease

9. Previous malignancy other than CRC in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix

10. Participation in another clinical trial within the past 30 days

11. Concurrent chronic systemic immune therapy or hormone therapy except physiologic replacement

12. Any unstable systemic disease, such as active infection, uncontrolled hypertension, unstable angina pectoris, angina in the last 3 months, cardiac failure of New York Heart Association classes ≥II, history of myocardial infarction, serious cardiac arrhythmias that require drug treatment, liver, kidney or metabolic disease in the last 6 months

13. Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease

14. severe bone marrow function failure

15. Any disease, metabolic disorders, or physical/laboratory examination suspected, or patients with high risk of complications

16. Known and declared history of human immunodeficiency virus(HIV)infection

17. HBV-DNA >1.0 × 103copy

18. Pregnancy or breastfeeding

19. Alcohol or drug abuse

20. Legal incapacity or limited legal capacity