A Study of Icotinib With Chemotherapy as Neoadjuvant Therapy for Patients With EGFRm Positive Resectable Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a Phase II, single-Arm, prospective study of neoadjuvant Icotinib with chemotherapy for the treatment of patients with epidermal growth factor receptor mutation positive, resectable for stage II to IIIB(N2) Non-small Cell Lung Cancer

Official Title
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A Phase II, Single-Arm, Prospective Study of Neoadjuvant Icotinib With Chemotherapy for the Treatment of Patients With Epidermal Growth Factor Receptor Mutation Positive, Resectable for Stage II to IIIB(N2) Non-small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Icotinib
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study. Male or female, at least 18 years of age. Histologically or cytologically documented lung adenocarcinoma within 60 days prior to study enrollment. Clinical stage IIA/IIB/IIIA/IIIB assessed by EBUS-TBNA or PET(positron emission tomography)/CT can be resected. EGFR mutation was detected by Amplification Refractory Mutation System(ARMS) and confirmed to be one of the 2 common EGFR mutations known to be associated with EGFR-TKI （epidermal growth factor receptor tyrosine kinase inhibitors）sensitivity (Ex19del, L858R). Presence of at least one accurately measurable lesion, CT showing a maximum diameter of 10mm at baseline (except for lymph nodes with a short axis of 15mm required) and suitable for accurate repeat measurements. Eastern Cooperative Oncology Group (ECOG) performance status （PS） of 0 or 1 at enrolment. Hematology , liver and kidney function are adequate for neoadjuvant therapy. Cardiopulmonary function suitable for surgical treatment (ECG, echocardiography, pulmonary function or blood gas analysis). Serum pregnancy test (for females of childbearing potential) negative at screening.Female patients of non-childbearing potential must meet at least 1 of the following criteria: ① Achieved postmenopausal status, defined as follows: cessation of regular menses forat least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle- stimulating hormone (FSH)level confirming the postmenopausal state; ② Have undergone a documented hysterectomy and/or bilateral oophorectomy; ③ Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations） are considered to be of childbearing potential. Male subjects must be willing to use barrier contraception Exclusion Criteria: Mixed squamous cell carcinoma, large cell carcinoma，small cell lung cancer. Prior treatment with any systemic anti-cancer therapy for NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug. Pregnant female patients; breastfeeding female patients. Current use of (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of Cytochrome P450 3A4(CYP3A4)(at least 3 weeks prior). Evidence of any severe or uncontrolled systemic disease, including uncontrolled hypertension and active bleeding, that the investigator considers to be detrimental to patient participation in the study or to adherence to the protocol. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV) or hepatitis C virus (HCV) (e.g., in case of known HBsAg or HCV antibody positivity), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness. Clinically significant cardiovascular disease, that is, active or within 3 months prior to enrollment: cerebral vascular accident/stroke, myocardial infarction, unstable angina,congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or third-degree Atrioventricular（AV）block (unless paced) or any AV block with PR >220 msec; or ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc(corrected QT interval) >470 msec, or congenital long QT syndrome. A history of hypersensitivity to Icotinib with or without active excipients or to drugs of similar chemical structure or class, and uncontrollable nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulated drugs, or having undergone major bowel resection that would interfere with adequate absorption of Icotinib. Past medical history of Interstitial lung disease（ ILD）, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. Inadequate bone marrow reserve (a leukocyte count less than 4000 mm3, a platelet count less than 100,000 mm3, and a hemoglobin level less than 10 g/dL); adequate renal function deficiency(not normal serum creatinine and blood urea nitrogen levels, and a creatinine clearance level 60 mg/minute); and an inadequate serum aspartate aminotransferase level more than 2.5 times the upper normal limit (UNL) and a serum alanine aminotransferase level more than 2.5 times the UNL.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Icotinib with platinum-based chemotherapy<br>Icotinib 125 mg TID plus investigator's choice of platinum-based standard of care chemotherapy (pemetrexed/carboplatin or pemetrexed/cisplatin) | Drug: Icotinib<br>* Oral<br>Drug: Cisplatin<br>* Cisplatin (75mg/m2) to be administered with pemetrexed on Day 1 of every 3-week cycle for 2 cycles.<br>Drug: Carboplatin<br>* Carboplatin (AUC5) to be administered with pemetrexed on Day 1 of every 3-week cycle for 2 cycles<br>Drug: Pemetrexed<br>* Pemetrexed (500 mg/m2) to be administered with cisplatin or carboplatin on Day 1 of every 3-week cycle for 2 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response (MPR) | Defined as ≤10% residual cancer cells in the main tumour, as assessed per central pathology laboratory post-surgery | From date of randomization to an average of 12 weeks after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) | Defined as absence of any residual cancer cells in the dissected tumour samples, including the main tumour and lymph nodes, assessed post-surgery | From date of randomization to an average of 12 weeks after the first dose | 
| Overall Survival (OS) | Defined as the time from the date of entry to the date of death from any cause. | Up to approximately 5.5 years after the last patient is randomized | 
| Disease free survival (DFS) | DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first. | From date of randomization up to approximately 42 months after date of resection | 
| Objective response rate(ORR) | ORR is defined as the percentage of participants having a complete response or a partial response, measured by RECIST 1.1. | Baseline (Prior to surgery) | 
| Disease control rate(DCR) | DCR is defined as the percentage of participants having a complete response , a partial response and disease stability measured by RECIST 1.1. | Baseline (Prior to surgery) | 
| R0 surgical resection rate | the proportion of resection margin without macroscopic or microscopic tumor residue (negative resection margin) | Post surgery (within one week) | 
| Incidence of Adverse Events | AE captured by CYCAE 5.0 | From the time of enrollment to either 28-days after the last dose of last study treatment for patients who do not undergo surgery, or 90-days post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resectable, NSCLC, Icotinib, EGFRm Positive, Neoadjuvant