Anlotinib Hydrochloride Combined With EGFR TKIs in Advanced Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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After the second-line treatment of patients with non-T790M mutations, chemotherapy with platinum-containing drugs was used, and chemotherapy-related toxicity was high. Studies have shown that bevacizumab combined with EGFR TKI have a good trend of benefit. This study is aimed to evaluate the efficacy and safety of Anlotinib Hydrochloride combined with first-generation EGFR TKIs as second-line treatment in advanced non-small cell lung cancer . The patients with IV non-small lung cancer have acquired resistance to prior first-generation EGFR TKIs and have non-T790M mutation.

Official Title
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A Prospective, Single-arm, Multicenter Study of Anlotinib Hydrochloride Combined With First-generation EGFR TKIs as Second-line Treatment in Acquired (Non-T790M Mutation) Resistance Advanced Non-small Cell Lung Cancer

Conditions
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Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Anlotinib Hydrochloride
* Drug: Gefitinib
* Drug: Icotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have histlogically confirmed stage IV non-small cell lung cancer . The initial treatment with gefitinib/icotinib evaluated PR/NC and the efficacy lasted for more than 6 months, then the disease progressed later. (The efficacy was assessed as PD according to the evaluation standard of RECIST1.1) At least a measurable lesion that meets the RECIST 1.1 criteria. Any gender. Age ≥18 years and ≤75 years Life expectancy >3 months. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. Previously, EGFR gene test showed EGFR exon 19 deletion or exon 21 (L858R) mutation, and the gene test showed no T790M mutation before enrollment. Adequate organ function: haemoglobin ≥ 90 g/L;neutrophils count ≥1.5×109/L; platelet count ≥ 90 × 109/L; total bilirubin ≤ 1.5 × ULN ;ALT < 2 × ULN, (ALT < 5 × ULN, for those with liver metastases);AST < 2 × ULN, (AST < 5 × ULN, for those with liver metastases); Cr≤1.5× ULN. Echocardiography : LVEF≥50% 12-leads electrocardiogram : QTcF<450ms (man), <470ms(woman) Patient informed consent and signed written consent Patient compliance was good and voluntary follow-up, treatment, laboratory testing, and other research steps were performed as planned. Exclusion Criteria: The patient has previously received anti-tumor therapy for EGFR TKIs other than gefitinib and ectinib for lung cancer. Patients that cannot detect EGFR gene, or patients with known T790M mutation. Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer). CT or MRI shows that the tumor lesion is ≤ 5 mm from the large vessel, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor. Active brain metastasis, cancerous meningitis, spinal cord compression patients. Other active malignancies that require simultaneous treatment. Has a history of malignant tumors in the past 5 years. Patients with previous anti-tumor treatment-related adverse reactions who have not recovered to NCI-CTC AE≤1. Abnormal coagulation ,with bleeding tendency or undergoing thrombolysis or anticoagulant therapy. Renal insufficiency: urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g, or creatinine clearance <60ml / min. Severe acute or chronic infection requiring systemic treatment. Suffering from severe cardiovascular disease: myocardial ischemia ,myocardial or arrhythmia. Clinically significant hemoptysis occurred within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or a clear tendency to hemorrhage. Untreated active hepatitis : Hepatitis B or Hepatitis C

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
Intervention Model: Single Group Assignment
Interventional Model Description: Anlotinib Hydrochloride Combined With gefitinib or Icotinib
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anlotinib Hydrochloride plus gefitinib or icotinib<br> | Drug: Anlotinib Hydrochloride<br>* Capsule, P.O. 12mg qd ,days 1-14, 21 days a cycle<br>Drug: Gefitinib<br>* Tablet, P.O. 250mg qd<br>Drug: Icotinib<br>* Tablet, P.O. 125mg tid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS（Progress free survival） | 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. | each 42 days up to PD or death(up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time until death due to any cause. | From randomization until death (up to 24 months) | 
| 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.prior to progression or any further therapy. | each 42 days up to intolerance the toxicity or PD (up to 24 months) | 
| Quality of Life(QoL) | use EORTC QLQ-C30(version 3) questionnaire to evaluate the quality of life. | each 42 days up to intolerance the toxicity or PD (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. | each 42 days up to intolerance the toxicity or PD (up to 24 months) |