Neo-adjuvant Treatment in Non-Small Cell Lung Cancer (NSCLC)

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying the side effects of giving cetuximab together with cisplatin and docetaxel before radiation therapy and cetuximab followed by surgery and to see how well it works in treating patients with stage IIIB non-small cell lung cancer that can be removed by surgery.

Detailed Description
-----------------
OBJECTIVES: To evaluate the efficacy and safety of neoadjuvant sequential chemoimmunotherapy comprising cetuximab, cisplatin, and docetaxel before radiotherapy and cetuximab followed by surgery in patients with resectable stage IIIB non-small cell lung cancer. OUTLINE: This is a multicenter study. Chemoimmunotherapy (courses 1-3): Patients receive chemoimmunotherapy comprising cetuximab IV over 1-2 hours on days 1, 8, and 15; cisplatin IV over 1 hour on days 1 and 2; and docetaxel IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) on days 3-8 or a single dose of pegfilgrastim the day after chemotherapy. Treatment repeats every 3 weeks for 3 courses. Radiotherapy (course 4): Beginning on day 1 of week 10, patients undergo 3-dimensional conformal or intensity-modulated radiotherapy 5 days a week for 3 weeks. Patients also receive cetuximab IV over 1 hour on days 1, 8, and 15. Surgery: Beginning 21-28 days after completion of radiotherapy, patients undergo surgery. After completion of study treatment, patients are followed every 3 months for 2 years and every 6 months for 3 years.

Official Title
-----------------
Preoperative Chemotherapy and Radiotherapy Concomitant to Cetuximab in Non-Small Cell Lung Cancer (NSCLC) Patients With IIIB Disease - A Multicenter Phase II Trial

Conditions
-----------------
Lung Cancer

Intervention / Treatment
-----------------
* Drug: cetuximab
* Drug: cisplatin
* Drug: docetaxel
* Radiation: Radiotherapy
* Procedure: Surgery


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed non-small cell lung cancer (NSCLC) Squamous, adeno, large cell, or poorly differentiated disease Stage IIIB disease (T4N0-3M0 or T1-4N3M0) according to 6th TNM classification Assessed by bronchoscopy and PET-CT scan within 42 days of registration No malignant pleural or pericardial effusion, invasion of the aorta, esophagus, myocardium, or supraclavicular No scalene nodes N3 No stages IIIB disease defined only by satellite lesions in the same lobe Lymph node staging done by mediastinoscopy (or EBUS) in N+ disease on PET-CT scan (SUV above mediastinum background SUV) or CT (size > 10 mm in the smallest diameter) within 42 days of registration Fine needle aspiration biopsy must be done by EBUS, TBNA, or VATS if lymph nodes are not accessible by mediastinoscopy (ATS nodes #5/6) Mediastinoscopy is mandatory for suspicion of T4 tumor invading the trachea on PET-CT and CT scan in N-disease Measurable disease assessed by contrast-enhanced CT-scan within 28 days of registration Tumor tissue available for translational research (no cytology) Resectable disease based on a multidisciplinary tumor board decision No brain metastasis (confirmed by MRI within 42 days of registration) PATIENT CHARACTERISTICS: WHO performance status 0-1 Platelet count ≥ 100 x 10^9/L Neutrophil count ≥ 1.5 x 10^9/L Bilirubin normal AST ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Creatinine clearance ≥ 60 mL/min FEV1 and DLCO ≥ 80% OR exercise test peak V02 > 75% or 20 mL kg^-1 min^-1 (for pneumonectomy) Exercise test peak V02 ≥ 35% and ≥ 10 mL kg^-1 min^-1 with predicted postoperative FEV1 and DLCO ≥ 30% (for resection less than pneumonectomy [resection up to calculated extend according to ESTS/ACCP guidelines]) Ejection fraction > 45% assessed by echocardiography Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 12 months after completion of study therapy Must be compliant and geographically proximal for proper staging and follow-up No previous malignancy within the past 5 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer No psychiatric disorder precluding understanding of information on trial-related topics and giving informed consent No preexisting peripheral neuropathy > grade 1 No ischemia or relevant dysfunction revealed by noninvasive stress testing (stress radionuclide myocardial perfusion imaging or dobutamine stress echocardiography) for patients with a history of ischemic heart disease or any other relevant cardiovascular condition No unstable cardiac disease requiring treatment, congestive heart failure or angina pectoris even if medically controlled, significant arrhythmia, or myocardial infarction within the past 3 months No serious underlying medical condition that, at the judgment of the investigator, could impair the ability of the patient to participate in the trial (e.g., active autoimmune disease, uncontrolled diabetes, or uncontrolled infection) No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs No absolute contraindications for the use of corticosteroids as premedication PRIOR CONCURRENT THERAPY: No prior radiotherapy to the chest No pretreatment with any cytostatic therapy No concurrent corticosteroids, except for prophylactic medication regimen prior to treatment or treatment of acute hypersensitivity reactions or chronic treatment (initiated > 6 months prior to trial entry) at low-dose (< 20 mg methylprednisolone or equivalent) No concurrent drugs contraindicated for use with the trial drugs At least 30 days since prior and no other concurrent experimental drugs or other anticancer therapy on another clinical trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab, Cisplatin, Docetaxel, Radiotherapy and Surgery<br> | Drug: cetuximab<br>* 400 mg/m2 initial dose on day 1 250 mg/m2 weekly starting on day 8 and for 12 weeks<br>* Other names: Erbitux;Drug: cisplatin<br>* 50 mg/m2 on day 1 and 2 of 21 day cycles, for 3 cycles<br>* Other names: Platin;Drug: docetaxel<br>* 85 mg/m2 day 1 of 21 day cycles, for 3 cycles<br>* Other names: Taxotere;Radiation: Radiotherapy<br>* 44 Gy (PTV1=30 Gy, PTV2=14 Gy), for 3 weeks, after the 3 cycles of Cisplatin / Docetaxel treatment<br>Procedure: Surgery<br>* Ipsilateral formal mediastinal lymphadenectomy. In case of involved N3 lymph nodes, resection of the precarinal and contralateral nodes.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | at 1 year (+/- 1 month) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related death during chemoimmunotherapy, radioimmunotherapy, and perioperatively |  | 30 days after surgery | 
| Metabolic response evaluated by PET |  | At baseline and after chemo-immunotherapy | 
| Response status after chemoimmunotherapy and radioimmunotherapy |  | After chemoimmunotherapy and after radioimmunotherapy | 
| Complete pathological response |  | After surgery | 
| Overall survival |  | At the end of the follow-up phase (max. 5 years after treatment termination or surgery) | 
| Adverse events |  | During the all trial treatment until 30 days after surgery or treatment stop | 
| Operability |  | Before trial treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IIIB non-small cell lung cancer, adenocarcinoma of the lung, adenosquamous cell lung cancer, large cell lung cancer, squamous cell lung cancer