Gefitinib With Anlotinib in Advanced Non-squamous NSCLC Patients With Uncleared Plasma ctDNA EGFRm After First-line Treatment With Gefitinib

Study Overview
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Brief Summary
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TKIs therapy is the first-line treatment of patients with EGFR mutation advanced NSCLC.However, some patients have poor prognosis of drug resistance in the early stage. The dynamic alterations of ctDNA-based EGFR mutation after TKIs treatment is a predictor of the efficacy of TKIs treatment, which can be used to identify this part of patients in the early stage.Drug resistance can be overcome when TKIs is combined with drugs in different mechanisms of action, such as chemotherapy and anti-angiogenesis therapy.Gefitinib is the first-generation oral EGFR TKIs. Anlotinib is a domestic oral small molecule inhibitor of multireceptor tyrosine kinase, which has extensive inhibitory effect on tumor angiogenesis and growth.Gefitinib combined with anlotinib is a new option in the treatment of patients with uncleared plasma EGFRm after gefitinib treatment.

Detailed Description
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This is an open-label, prospective, randomized, controlled phase II clinical trial.To evaluate the efficacy and safety of gefitinib combined with anlotinib versus gefitinib alone in advanced non-squamous NSCLC patients whose EGFRm was not cleared in plasma ctDNA after 8 weeks of gefitinib first-line treatment, so as to provide clinical basis for a new and tolerable treatment that can prolong the survival time of patients with advanced NSCLC. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. The efficacy and adverse reactions of the trial regimen will be evaluated according to RECIST criteria and NCI-CTC AE V3.0.

Official Title
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A Randomized Phase II Trial of Gefitinib With Anlotinib in Advanced Non-squamous NSCLC Patients With Uncleared Plasma ctDNA EGFRm After First-line Treatment With Gefitinib

Conditions
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Non-small Cell Lung Cancer, EGFR Gene Mutation

Intervention / Treatment
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* Drug: Gefitinib
* Drug: Anlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed that EGFR sensitive mutation (ex19del or L858R mutation) in tumor tissue was detected by non-squamous NSCLC, and EGFR mutation (ex19del or L858R mutation) in ctDNA before treatment; Staging is IVB stage (AJCC 8th Edition) ; According to the comprehensive judgment of many disciplines, it is impossible to be treated by operation; PS score 0-1; The patient has at least one measurable tumor injury (the tumor is considered unmeasurable at the site of previous radiotherapy); Systemic anti-tumor therapy such as chemotherapy, immunotherapy and targeted therapy were not performed before entering the group; There is no history of malignant tumor and no serious medical disease; FEV1 ≥ 1.2L/ seconds or ≥ 50% predicted value; Laboratory examination: White blood cell count ≥ 4 *10^9/L, neutrophil count ≥ 2.0 *10^9, platelet count ≥ 100 *10^9, hemoglobin ≥ 10 g / L, liver and kidney function and ECG were normal; The pregnancy test was negative within 3 days before entering the group, and agreed to use medically effective contraceptive measures during the trial; Life expectancy is more than 12 weeks; Sign informed consent form; cooperate with regular follow-up. Exclusion Criteria: T4 (AJCC 8th Edition) patients with severe destruction and stenosis of large vessels confirmed by imaging; Clinical severe infection (> grade 2 NCI-CTC V3.0); Severe immunosuppressive disease; The patient's physical condition is life-threatening; A pregnant or breastfeeding patient. Female patients who are likely to become pregnant must be tested negative within 7 days of the start of treatment before continuing. Patients enrolled in the trial (both male and female) must use contraception during the trial period until two weeks after the trial is completed; PS score ≥ 2; At the same time, there are other serious diseases (congestive heart failure, transmural myocardial infarction, COPD or other respiratory diseases that affect treatment, etc.), considering that the study may aggravate or fail to control the disease; Those who have suffered or are currently suffering from tumors whose primary site or histology are different from those evaluated in this study. Excluding cervical carcinoma in situ, cured basal cell carcinoma, bladder surface tumor [Ta,Tis&T1], or any cured tumor that has been in the study for more than 3 years; The patient refused to participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefitinib with Anlotinib<br>If persistence of plasma ctDNA EGFRm after 8 weeks of gefitinib first-line treatment, Gefitinib 250mg oral daily and Anlotinib 10mg oral d1-14, every 3 weeks | Drug: Gefitinib<br>* If persistence of plasma ctDNA EGFRm after 8 weeks of gefitinib first-line treatment<br>* Other names: Iressa;Drug: Anlotinib<br>* If clearance of plasma ctDNA EGFRm after 8 weeks of gefitinib first-line treatment<br>* Other names: AL3818;|
| Experimental: Gefitinib<br>If clearance of plasma ctDNA EGFRm after 8 weeks of gefitinib first-line treatment, Gefitinib 250mg oral daily | Drug: Gefitinib<br>* If persistence of plasma ctDNA EGFRm after 8 weeks of gefitinib first-line treatment<br>* Other names: Iressa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival, PFS | The period from the start of treatment to the progression or death of a patient | Every 6 weeks up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival, OS | time from the beginning of study to death due to any cause or last follow-up | Every 6 weeks up to 2 years, and then every 3 months up to 5 years | 
| Objective Response Rate, ORR | ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR) | 6 weeks after treatment | 
| adverse events | Number of patients with adverse events (AEs) as a measure of safety and tolerability | Every 6 weeks up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gefitinib, Anlotinib, EGFR Gene Mutation, Non-small Cell Lung Cancer, TKIs, Antivascular therapy