A Study of Anlotinib Hydrochloride Capsule Combined With Chemotherapy as First-line Treatment in Subjects With RAS/BRAF Wild Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is an open label, randomized, phase Ⅲ study to treat subjects with RAS/BRAF wild-type, unresectable metastatic colorectal cancer. The patients will be randomized into two arms consist of Anlotinib (3 weeks/cycle) + CapeOx and Bevacizumab (3 week/cycle) + CapeOx at a ratio of 1:1. This study is conducted to assess the efficacy and safety of Anlotinib and Chemotherapy as first-line treatment in subjects with RAS/BRAF wild-type Metastatic Colorectal Cancer.

Official Title
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A Randomized, Open-label, Parallel Controlled, Multi-center Phase III Study of Anlotinib Hydrochloride Capsule Combined With Chemotherapy as First-line Treatment in Subjects With RAS/BRAF Wild Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Anlotinib hydrochloride capsule
* Drug: Bevacizumab
* Drug: Oxaliplatin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Understood and Signed an informed consent form. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1；Life expectancy≥ 3 months. 3. Histologically or cytologically confirmed unresectable metastatic colorectal cancer. 4. Has RAS/BRAF wild-type. 5. Has at least one measurable lesion. 6. Adequate organ function. 7.Male or female subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study (such as intrauterine devices , contraceptives or condoms) ; No pregnant or breastfeeding women, and a negative pregnancy test are received within 7 days before the randomization. Exclusion Criteria: 1.Has dMMR/MSI-H. 2. Combined with the following diseases or medical history: Previous or co-existing malignancies within 3 years except for cured cervical carcinoma in situ, non-melanoma skin cancer and superficial bladder tumors； Has many factors that affect the oral administration of drugs； Has Gastrointestinal bleeding or perforation within 4 weeks before the first dose； Has active inflammatory bowel disease within 4 weeks before the first dose； Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage； Patients whose adverse events (except hair loss) caused by previous treatment did not recover to ≤CTCAE 1 degree； Has received major surgical procedure、biopsy or obvious traumatic injury within 28 days before the first dose； Imaging (CT or MRI) shows that tumor invades large blood vessels or the boundary of blood vessels is unclear； Has any bleeding event or the level of bleeding events ≥ CTCAE 3； Has unhealed wounds, ulcerative or fractures； Has arterial or venous thromboembolic events occurred within 6 months, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis and pulmonary embolism； Has a history of psychotropic substance abuse and are unable to quit ； Has any severe and / or uncontrolled disease； 3.Tumor related symptoms and treatment Has received chemotherapy, surgery, radiotherapy, and other anti-cancer therapy within 4 weeks before the first dose. Has received anti-tumor Chinese patent medicine which were approved by NMPA Within 2 weeks before the first dose. Previous adjuvant therapy containing anti-vascular or anti-EGFR targeted drugs. Has received systematic treatment for advanced colorectal cancer. Has symptomatic brain metastases or control of symptoms < 2 month. 4.Has participated in other anticancer drug clinical trials within 4 weeks. 5.According to the judgement of the researchers, there are other factors that may lead to the termination of the study.

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: Anlotinib + CapeOx<br>Anlotinib combined with CapeOx(Oxaliplatin+Capecitabine) were used for 4-8 cycles, each cycle is 3 weeks. After 8 cycles, the regimen is changed to Anlotinib combined with Capecitabine. | Drug: Anlotinib hydrochloride capsule<br>* Anlotinib hydrochloride capsule 12mg given orally in fasting conditions, once daily in 21-day cycle (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21)；<br>Drug: Oxaliplatin<br>* Oxaliplatin 130mg/m2, intravenous drip, on Day 1；<br>Drug: Capecitabine<br>* Capecitabine 850mg/m2 administrated orally twice daily from Day 1-14.<br>|
| Active Comparator: Bevacizumab + CapeOx<br>Bevacizumab combined with CapeOx(Oxaliplatin+Capecitabine) were used for 4-8 cycles, each cycle is 3 weeks. After 8 cycles, the regimen is changed to Bevacizumab combined with Capecitabine. | Drug: Bevacizumab<br>* Bevacizumab 7.5mg/kg, intravenous drip, on Day 1<br>Drug: Oxaliplatin<br>* Oxaliplatin 130mg/m2, intravenous drip, on Day 1；<br>Drug: Capecitabine<br>* Capecitabine 850mg/m2 administrated orally twice daily from Day 1-14.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) assessed by IRC | PFS defined as the time from randomization until the first documented progressive disease (PD) or death from any cause. | Baseline up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS defined as the time from first dose until the first documented progressive disease (PD) or death from any cause. | Baseline up to 15 months | 
| Overall survival (OS) | OS defined as the time from the first dose to death from any cause. Survival time was censored at the date of last contact for patients who were still alive or lost to follow-up. | Baseline up to 20 months | 
| Objective Response Rate（ORR） | Percentage of subjects achieving complete response (CR) and partial response (PR) . | Baseline up to 15 months | 
| Disease Control Rate (DCR) | Percentage of subjects achieving complete response (CR) and partial response (PR) and stable disease (SD). | Baseline up to 15 months | 
| Duration of Response (DOR) | DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. | Baseline up to 15 months |