Gefitinib and Berberine in the First-line Treatment of Lung Adenocarcinoma With EGFR Mutation

Study Overview
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Brief Summary
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Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 11 months when treated with gefitinib. Combination of gefitinib and berberine could improve efficacy in lung cancer with EGFR mutation in vivo and vitro. The investigators hypothesize that progression-free survival could be improved by combination of gefitinib and berberine.

Detailed Description
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Strong lipogenic activity and high expression of sterol regulatory element-binding protein 1 (SREBP-1) were found in gefitinib-resistance NSCLC cells. Berberine, an effective suppressor of SREBP1 and lipogenesis regulated through ROS/AMPK pathway, selectively inhibited the growth of gefitinib-resistance NSCLC cells but not that of normal cells. It effectively caused mitochondrial dysfunction, activated reactive oxygen species (ROS)/AMPK pathway and finally suppressed cellular lipogenesis and cell proliferation. Addition of ROS blocker, AMPK inhibitor and palmitic acid significantly reduced the effect of Berberine. In in vivo study, treatment of Berberine led to significant inhibition of mouse tumor xenograft growth.

Official Title
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An Open-label Phase II Trial of Gefitinib and Berberine in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Conditions
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Lung Adenocarcinoma, EGFR Mutation

Intervention / Treatment
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* Drug: gefitinib
* Drug: Berberine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years ECOG performance status 0-2 Adequate haematological function, coagulation, liver function and renal function Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer (NSCLC) TNM version 7 stage IV disease including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease not amenable to curative treatment (including patients progressing after radiochemotherapy for stage III disease) Measurable or evaluable disease (according to RECIST 1.1 criteria). Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R) Exclusion Criteria: Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. Patients with any known significant ophthalmologic anomaly of the ocular surface Patients who received prior chemotherapy for metastatic disease Patients who received previous treatment for lung cancer with drugs targeting EGFR or VEGF Pregnancy

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefitinib and Berberine<br>Experimental: Gefitinib and Berberine Patients will be treated with Gefitinib and Berberine. Gefitinib: 250 mg p.o., daily. Berberine: 50 mg p.o., tid. | Drug: gefitinib<br>* Patients will be treated with gefitinib, 250 mg p.o., daily<br>* Other names: Iressa (AstraZeneca);Drug: Berberine<br>* Patients will be treated with Berberine, 50 mg p.o., tid<br>* Other names: Berberine Sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Time from the date of enrolment to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal and death) | Within 6 months of the last visit of last patient, approximately 30 months after inclusion of first patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response | Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment. | through study completion,an average of three years | 
| safety | Adverse events graded according to NCI CTCAE V4. | Within 6 months of the last visit of last patient, approximately 30 months after inclusion of first patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Adenocarcinoma, EGFR mutation, Gefitinib, Berberine