Anlotinib Versus Docetaxel as the Second-line Treatment in EGFR Wild Type Patients With Advanced NSCLC

Study Overview
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Brief Summary
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This study is conducted to explore the safety and efficacy of anlotinib, a tyrosine kinase inhibitors of Vascular Endothelial Growth Factor Receptor 2（VEGFR）、FGFR（Fibroblast Growth Factor Receptor）, Platelet-derived growth factor Receptor（PDGFR） and c-kit, vs docetaxel in advanced Non-squamous Non-small cell lung cancer harbouring wild-type epidermal growth factor receptor (EGFR) .

Detailed Description
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This is a multicentre randomised controlled clinical trial conducted in China to compare the efficacy and and safety of Anlotinib vs Docetaxel in patients of EGFR mutation-negative advanced nonsquamous non-small Cell Lung Cancer. Eligible patients will be randomized to arm A and arm B: Arm A: Patients on the anlotinib arm received 12mg anlotinib orally daily on day 1 to 14 of a 21-day cycle. Arm B: Patients on the docetaxel arm received 75mg/m2 docetaxel as intravenous infusion on day 1 of a 21-day cycle.

Official Title
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Efficacy and Safety of Anlotinib Versus Docetaxel in Advanved Non-squamous Non-small-cell Lung Cancer Without EGFR Mutation Who Failed in First-line Platinum-based Doublet Chemotherapy: an Open, Muti-center, Randomized Controlled Trial

Conditions
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Lung Cancer, Lung Cancer Metastatic

Intervention / Treatment
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* Drug: Anlotinib Hydrochloride
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -≥ 18 and ≤ 70 years of age. Signed the informed consent form prior to patient entry Histologically or pathologically confirmed non-squamous non-small cell lung cancer(NSCLC) with stage IV . Histologically or pathologically confirmed non-squamous non-small cell lung cancer(NSCLC) with stage IV . Patients who has failed from the first-line Platinum-based Doublet chemotherapy harbouring epidermal growth factor receptor(EGFR) sensitive mutations negetive, confirmed by pathological or blood test results) ）,ALK/ROS1 mutation-negative or unknown (For recurrent patients, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility, and the last treatment time must be more than 6 months before enrollment） Noted: failed from prior treatment means(1) progress disease confirmed by CT; cannot tolerable from standard treatment, such as hematologic toxicities ≥ level 4; non-hematologic toxicities ≥ level 3;damages of heart/liver/kidney ≥ level 2 in CTC AE 4.0 Must have at least one measurable lesion as per RECIST 1.1 defined as a lesion that is 10mm in longest diameter imaged by CT scan or MRI；prior topical treatment, such as radiotherapy cryosurgery to the lesions is not allowed in less than 3 months; Life expectancy ≥3 months. Eastern Cooperative Oncology Group(ECOG) performance status 0 or 1. Toxicity caused by prior anti-cancer treatments was restored to ≤ level 1 in CTC AE (4.0) , except alopecia; The blood routine examination need to be standard (no blood transfusion and blood products within 14 days, no g-csf and other hematopoietic stimulating factor correction); Hemoglobin（HB）≥90 g/L; A Neutrophil count of （ANC）≥1.5×10e9/L; A Platelet count of （PLT）≥80×10e9/L; A Total bilirubin (TBil) of ≤1.5 upper normal limitation (UNL); A alanine aminotransferase (ALT) and a aspartate aminotransferase (AST) of ≤2.5 UNL, in case of liver metastasis ALAT and ASAT≤5 UNL; A creatinine (Cr) of ≤1.5 UNL; a creatinine clearance rate ≥ 60ml/min (Cockcroft-Gault); The woman patients of childbearing age who must agree to take contraceptive methods during the research and within another 8 weeks after it and examined as negative in blood serum test or urine pregnancy test within 7 days before the research; the man patients who must agree to take contraceptive methods during the research and within another 8 weeks Voluntarily joined the study and signed informed consent, with good compliance and follow-up. Exclusion Criteria: -Mixed Lung Cancer (including small cell cancer and other kinds of cancer mixed with non-small cell cancer, adenocarcinoma mixed with squamous cell carcinoma No squamous NSCLC with hemoptysis (>50ml/day); Treated by taxel or similar drugs in 12months; symptoms of brain metastases cannot be controlled and treated within less than 2 months Tumor locate within a distance of less than 5 mm from the large vessels, less than 2 cm from the bronchial tree, or has invaded local large vessels; tumor with cavum or necrotic obviously; Uncontrolled hypertension (systolic ≥140mmHg and/or diastolic ≥90mmHg, despite optimal drug therapy). Patients with with grade Ⅱ myocardial ischemia or myocardial infarction, poor control of arrhythmias (including QTc interval male ≥ 450 ms, female ≥470 ms); according to NYHA standard, grade Ⅲ   Ⅳ heart failure, or cardiac color Doppler ultrasound examination showed left ventricular ejection fraction (LVEF) <50%. Coagulation dysfunction (INR> 1.5, PT> ULN +4s or APTT> 1.5 ULN), with bleeding tendency or ongoing thrombolysis or anti-blood coagulation treatment;note: Note: under the premise of International Normalized ratio (INR) of prothrombin time (PT) Less than or equal to 1.5, allow to administrate low-dose heparin (adult daily dose is 06000   12000 U) or low-dose aspirin (100 mg daily dosage or less) , for prophylactic purposes Patients whose routine urine tests indicate that urine protein ≥ ++ or verifies that the 24-h urine protein quantitation ≥ 1.0 g. Patients whose has peripheral neuropathy over level 2 in CTC AE4.0, except trauma. Patients with respiratory syndrome (difficulty breathing of level 2 or higher ), serous cavity effusion need to surgical treatment ( including pleural of level 2 or higher with respiratory distress and anoxia Patients who have unhealed wounds or fractures for a long time. Patients with severe infections , and need to receive systemic antibiotic treatment Decompensated diabetes or other contraindication with high dose glucocorticoid therapy; Cirrhosis or decompensated liver disease; active or untreated hepatitis C and/or Hepatitis B virus (HBV) infection（prior hepatitis B history, HBsAg positive and HBV DNA≥500IU/mL; HCV RNA positive and hepatic Insufficiency Has an obvious factor influencing oral drug absorption, such as unable to swallow, chronic diarrhea and intestinal obstruction, etc Patients who received major surgical operations or experienced severe traumatic injuries, bone fracture, or ulcers within 4 weeks before screening. Severe weight loss (> 10%) Within 6 weeks before Random Patients who had obvious hemoptysis (>50ml/day) within 3 months before screening; Patients who experienced bleeding symptoms of clinical significance within 3 months before screening, or with confirmed bleeding tendency such as hemorrhage of digestive tract, hemorrhagic gastric ulcer, baseline occult blood in stool ++ and above, or vasculitis, etc; Patients who manifested arterial/venous thrombus events, e.g. cerebrovascular accident (including transient ischemic attack), deep venous thrombosis and pulmonary embolism, etc., within 12 months before screening. Allergic reactions to anotol or excipients in experimental drugs. Allergic reactions to contrast medium Patients have participated in other antitumor drug clinical trials Within 4 weeks before enrollment or prepare to receive systemic anti-tumor treatment during the study or Within 4 weeks before randomization Patients with any other medical condition or reason, in that investigator's opinion, makes the patient unstable to participate in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 hydrochloric<br>Anlotinib (12mg QD PO d1-14, 21 days per cycle) | Drug: Anlotinib Hydrochloride<br>* Anlotinib (12mg QD PO d1-14, 21 days per cycle)<br>|
| Experimental: Docetaxel<br>Docetaxel (75mg/m2 IV d1, 21 days per cycle) | Drug: Docetaxel<br>* Docetaxel (75mg/m2 IV d1, 21 days per cycle)<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 first dose of study treatment until the first date of either objective disease progression or death due to any cause. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate(ORR) | ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1. | Up to 24 months | 
| Disease Control Rate (DCR) | Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1. | Up to 24 months |