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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: CMAB009
* Drug: Irinotecan
* Drug: Folinic acid
* Drug: 5-fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, Aged ≥18 years and ≤75 years Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum First occurrence of metastatic disease(not curatively resected) RAS/BRAF wild-type status in tumor tissue At least one measurable lesion by computer tomography(CT) or magnetic resonance imaging (MRI)according to RECIST1.1 criteria (not in an irradiated area) Eastern Cooperative Oncology Group(ECOG)performance status of 0 or 1 at trial entry Life expectancy of at least 3 months 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) Recovery from relevant toxicity due to previous treatment before trial entry Signed the informed consent form voluntarily Exclusion Criteria: Radiotherapy or surgery（excluding prior diagnostic biopsy）in the 30 days before trial treatment 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 Previous chemotherapy for CRC adjuvant treatment if terminated <12 months before diagnosis of recurrence or metastatic disease 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) Known hypersensitivity or allergic reactions against any of the components of the trial treatments History of organ allograft, autologous stem cell transplantation, or allogeneic stem cell transplantation Other non-permitted concomitant anti-cancer therapies Known brain metastasis and/or leptomeningeal disease Previous malignancy other than CRC in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix Participation in another clinical trial within the past 30 days Concurrent chronic systemic immune therapy or hormone therapy except physiologic replacement 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 Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease severe bone marrow function failure Any disease, metabolic disorders, or physical/laboratory examination suspected, or patients with high risk of complications Known and declared history of human immunodeficiency virus(HIV)infection HBV-DNA >1.0 × 103copy Pregnancy or breastfeeding Alcohol or drug abuse Legal incapacity or limited legal capacity

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CMAB009 + FOLFIRI<br>Drug: CMAB009(recombinant chimeric anti-EGFR monoclonal antibody injection), will be administered every 7 days at an initial dose of 400mg/m^2 and 250mg/m^2 for subsequent infusions until progression of disease , withdrawal of consent, or unacceptable toxicity. Drug: Irinotecan bi-weekly irinotecan infusion of 180mg/m^2 on Day 1. Drug: Folinic Acid infusion 400mg/m^2 of folinic acid in on Day 1. Drug: 5-Fluorouracil bolus 5-Fluorouracil bolus of 400mg/m^2 followed by a 46-48 h continuous infusion of 2400mg/m^2. every 2 weeks until progression of disease , withdrawal of consent, or unacceptable toxicity. | Drug: CMAB009<br>* for injection only<br>* Other names: Eribitux;Drug: Irinotecan<br>* for injection only<br>* Other names: Camptosar;Drug: Folinic acid<br>* for injection only<br>* Other names: leucovorin;Drug: 5-fluorouracil<br>* for injection only<br>* Other names: Fluoroplex;|
| Active Comparator: FOLFIRI<br>FOLFIRI Drug: Irinotecan bi-weekly irinotecan infusion of 180mg/m^2 on Day 1. Drug: Folinic Acid infusion 400mg/m^2 of folinic acid in on Day 1. Drug: 5-Fluorouracil bolus 5-Fluorouracil bolus of 400mg/m^2 followed by a 46-48 h continuous infusion of 2400mg/m^2. every 2 weeks until progression of disease , withdrawal of consent, or unacceptable toxicity. | Drug: Irinotecan<br>* for injection only<br>* Other names: Camptosar;Drug: Folinic acid<br>* for injection only<br>* Other names: leucovorin;Drug: 5-fluorouracil<br>* for injection only<br>* Other names: Fluoroplex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Defined as the duration from randomization until the date of first documented progression or date of death from any cause when death occurred within 90 days of randomization or the last tumor assessment, whichever was later. Progressive disease assessed by RECIST1.1 | Baseline up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate(ORR) | Defined as the percentage of subjects having achieved confirmed Complete Response + Partial Response as the best overall response based on RECIST1.1 | Baseline up to 24 months | 
| Overall Survival Time (OS) | Defined as the time from randomization to death | Baseline up to 48 months | 
| Duration of Response | Defined as the time from first assessment of CR or PR to disease progression or death | Baseline up to 24 months | 
| Number of Subjects with Curative Surgery of Liver Metastases | Defined as the number of subjects who underwent liver metastatic surgery with all lesions been resected completely after start of treatment | Baseline up to 12 months | 
| Quality of Life Assessment | EORTC-QLQ-C30 | Baseline up to 24 months | 
| Pharmacokinetic Parameters | Area under the curve and the Maximum concentration of CMAB009 | Baseline up to 50 days | 
| Incidence of anti-CMAB009 antibody | The incidence rate of ADA （anti-CMAB009 antibody）and Nab（neutralizing antibody） | baseline up to 32 weeks |