A Efficacy and Safety Study of Anlotinib Hydrochloride Capsule Combined With Chemotherapy Versus Placebo Combined With Chemotherapy as First-line Treatment in Subjects With Advanced Non-squamous Cell Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a randomized, double-blind, multicenter phase III clinical study to evaluate efficacy and safety of anlotinib hydrochloride capsule combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment in subjects with advanced non-squamous cell non-small cell lung cancer.

Official Title
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A Randomized, Double-blind, Multicenter Phase III Study of Anlotinib Hydrochloride Capsule Combined With Chemotherapy Versus Placebo Combined With Chemotherapy as First-line Treatment in Subjects With Advanced Non-squamous Cell Non-small Cell Lung Cancer

Conditions
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Advanced Non-squamous Cell Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Anlotinib hydrochloride capsule
* Drug: Carboplatin injection
* Drug: Pemetrexed disodium f Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Local advanced (stage IIIB / ⅢC), metastatic or recurrent (stage IV) non-squamous cell non-small cell lung cancer, has at least one measurable lesion. 2. EGFR, ALK, and ROS1 test results are negative. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, life expectancy≥ 12 weeks. 4. Has not received systemic anti-tumor treatment for advanced disease. 5.Adequate organ system function. 6. 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. 7. Understood and signed an informed consent form. Exclusion Criteria: 1.Other histopathological types of non-small cell lung cancer. 2.Has received VEGF pathway targeted therapy including anlotinib and bevacizumab. 3. Has multiple factors affecting oral medication. 4. Has symptomatic brain metastases. 5. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. 6. Has adverse events caused by previous therapy except alopecia that did not recover to ≤grade 1. 7. Has any severe and / or uncontrolled diseases. 8. Has any bleeding symptoms or treated with anticoagulants or vitamin K antagonists. 9.Has received surgery, or unhealed wounds within 4 weeks before the first administration. 10. Has hemoptysis within 28 days before randomization. 11. Imaging (CT or MRI) shows that tumor invades large blood vessels or the boundary with blood vessels is unclear. 12. Has arterial or venous thromboembolic events occurred within 6 months, such as cerebrovascular accident including transient ischemic attack, deep vein thrombosis and pulmonary embolism. 13. Has psychotropic substances abuse or a mental disorder. 14. Have a history of immunodeficiency. 15. Has received allogeneic organ transplantation, hematopoietic stem cell transplantation or bone marrow transplantation. 16. Has other malignancy. 17.Has participated in other anticancer drug clinical trials within 4 weeks. 18.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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anlotinib hydrochloride capsule + chemotherapy<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) + Carboplatin injection (AUC 5mg/mL/min, intravenous drip, on Day 1) + Pemetrexed disodium f Injection (500mg / m2, intravenous drip, on Day 1). | 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: Carboplatin injection<br>* Carboplatin injection AUC 5mg/mL/min, intravenous drip, on Day 1 in 21-day cycle.<br>Drug: Pemetrexed disodium f Injection<br>* Pemetrexed disodium f Injection 500mg / m2, intravenous drip, on Day 1 in 21-day cycle.<br>|
| Placebo Comparator: Placebo + chemotherapy<br>Placebo 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) + Carboplatin injection (AUC 5mg/mL/min, intravenous drip, on Day 1) + Pemetrexed disodium f Injection (500mg / m2, intravenous drip, on Day 1). | Drug: Carboplatin injection<br>* Carboplatin injection AUC 5mg/mL/min, intravenous drip, on Day 1 in 21-day cycle.<br>Drug: Pemetrexed disodium f Injection<br>* Pemetrexed disodium f Injection 500mg / m2, intravenous drip, on Day 1 in 21-day cycle.<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | PFS defined as the time from randomization until the first documented progressive disease (PD) or death from any cause. | up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) assessed by Independent Review Committee (IRC) | Percentage of subjects achieving complete response (CR) and partial response (PR) based on IRC. | up to 48 weeks | 
| 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. | up to 48 weeks | 
| Disease control rate（DCR） | Percentage of subjects achieving complete response (CR) and partial response (PR) and stable disease (SD). | up to 48 weeks | 
| Disease of Response (DOR) | DOR defined as time from earliest date of disease response to earliest date of disease progression based on radiographic assessment. | up to 48 weeks |