Chemotherapy and Radiation Therapy With or Without Panitumumab in Treating Patients With Stage IIIA Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy (CT), such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy (RT) uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as panitumumab, 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. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without panitumumab in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase II trial is studying chemotherapy and radiation therapy to see how well they work when given with or without panitumumab in treating patients with stage IIIA non-small cell lung cancer.

Detailed Description
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OBJECTIVES: Primary Determine the mediastinal nodal clearance after completion of induction chemoradiotherapy with or without panitumumab in patients with stage IIIA non-small cell lung cancer. Secondary Assess overall survival of these patients. Evaluate patterns of first failure in these patients. Determine the acute and late adverse events associated with these regimens. Assess surgical morbidities in patients with resectable disease at reassessment. Determine the correlation between pre- and post-treatment biomarkers (including epidermal growth factor receptor (EGFR) and ras mutation status) and outcomes (mediastinal nodal clearance and overall survival). Evaluate the prognostic value of plasma osteopontin and microRNA for overall survival. Assess the ability of FDG-PET/CT scan re-staging to predict outcome. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive induction therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Patients also undergo intensity-modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT) once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Beginning approximately 6-12 weeks later, patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21. Arm II: Patients receive induction therapy comprising panitumumab IV over 1 hour on days 1, 8, 15, 22, 29, and 36 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 8, 15, 22, 29, and 36. Patients also undergo IMRT or 3D-CRT once daily on days 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. Beginning approximately 6-12 weeks later, patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21. In both arms, patients with resectable disease and no disease progression may proceed to surgery (thoracotomy, lobectomy, or pneumonectomy) approximately 4-6 weeks after completion of induction therapy. After surgery, patients proceed to consolidation therapy. After completion of study treatment, patients are followed up at 6 weeks, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Official Title
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Randomized Phase II Study of Pre-operative Chemoradiotherapy +/- Panitumumab (IND #110152) Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIA, N2+) Non-Small Cell Lung Cancer

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: panitumumab
* Drug: carboplatin
* Drug: paclitaxel
* Procedure: surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed* non-small cell lung cancer (NSCLC), including any of the following histologies: Adenocarcinoma Adenosquamous Large cell carcinoma Squamous cell carcinoma Non-lobar and non-diffuse bronchoalveolar cell carcinoma NSCLC not otherwise specified NOTE: *Documentation of NSCLC may originate from the mediastinal node biopsy or aspiration Stage IIIA (T1-T3) disease with a single primary lung parenchymal lesion AND positive ipsilateral mediastinal node or nodes (N2) with or without positive ipsilateral hilar nodes (N1) N2 nodes must be separate from primary tumor by either CT scan or surgical exploration Maximum nodal diameter of involved N2 nodes cannot exceed 3.0 cm N2 status must be pathologically confirmed to be positive by one of the following methods*: Mediastinoscopy Mediastinotomy (Chamberlain procedure) Transesophageal needle biopsy using endoscopic ultrasound (EUS-TBNA) Endobronchial ultrasound biopsy using endoscopic ultrasound guidance (EBUS-TBNA) Thoracotomy Video-assisted thoracoscopy Transbronchial needle biopsy by Wang technique (TBNA) Fine-needle aspiration under CT guidance NOTE: *PET positivity in the ipsilateral mediastinal lymph nodes is not sufficient to establish N2 nodal status Ipsilateral mediastinal nodes associated with right-sided tumor must be biopsied unless all of the following are true: Tumor is left sided Paralyzed left true vocal cord documented by bronchoscopy or indirect laryngoscopy Nodes visible in the anterior/posterior (level 5) region on CT scan Distinct primary tumor separate from nodes visible on CT scan Histologic (biopsy) or cytologic (needle aspiration or sputum) proof of non-small cell histology from the primary tumor If lymph nodes in the contralateral mediastinum and neck are visible on contrast CT scan of the chest and are > 1.0 cm in short axis or if contralateral involvement is suggested by PET scan, then the nodes must be confirmed to be negative Measurable disease as determined by contrast-enhanced CT scan Primary lung tumor distinct from mediastinal lymph nodes If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable M1a disease): When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative. Exudative pleural effusions are excluded, regardless of cytology; Effusions that are minimal (i.e. not visible under ultrasound guidance) that are too small to safely tap are eligible. No palpable lymph nodes in the supraclavicular areas or higher in the neck, unless proven to be benign by fine-needle aspiration or biopsy No distant metastases PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Absolute neutrophil count (ANC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10.0 g/dL (transfusion allowed) Creatinine clearance ≥ 60 mL/min Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Serum albumin > 3.0 g/dL Serum magnesium normal (supplementation allowed) Not pregnant Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of treatment Forced expiratory volume at one second (FEV1) ≥ 2.0 L OR predicted post-resection FEV1 ≥ 0.8 L Diffusion capacity ≥ 50% predicted No other invasive malignancy within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the breast, oral cavity, or cervix No severe, active co-morbidity, including any of the following: Current uncontrolled cardiac disease (e.g., uncontrolled hypertension, unstable angina, myocardial infarction within the past 6 months, uncontrolled congestive heart failure, or cardiomyopathy with decreased ejection fraction (<50%) Acute bacterial or fungal infection requiring IV antibiotics Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or that would preclude study therapy within the past 4 weeks Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects AIDS or known HIV positivity No unintentional weight loss ≥ 5% of body weight within the past 6 months No prior severe infusion reaction to a monoclonal antibody No pre-existing peripheral neuropathy ≥ grade 2 PRIOR CONCURRENT THERAPY: No prior systemic chemotherapy or biological therapy (including erlotinib hydrochloride or similar agents) for the study cancer Prior chemotherapy for a different cancer allowed No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields No prior therapy that specifically and directly targets the EGFR pathway

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Induction CT+RT<br>Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin) | Drug: carboplatin<br>* Induction: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, AUC=6, IV, days 1 and 22.<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Induction: 50 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, 200 mg/m2, IV, days 1 and 22.<br>* Other names: Abraxane;Procedure: surgery<br>* A lobectomy or pneumonectomy performed 4-6 weeks after completion of induction chemoradiation<br>* Other names: pneumonectomy;|
| Experimental: Induction CT+RT+Panitumumab<br>Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin) | Drug: panitumumab<br>* Induction: 2.5 mg/kg, IV, days 1, 8, 15, 22, 29, 36 of radiation therapy before administration of chemotherapy and radiation therapy.<br>* Other names: Vectibix;Drug: carboplatin<br>* Induction: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, AUC=6, IV, days 1 and 22.<br>* Other names: Paraplatin;Drug: paclitaxel<br>* Induction: 50 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, 200 mg/m2, IV, days 1 and 22.<br>* Other names: Abraxane;Procedure: surgery<br>* A lobectomy or pneumonectomy performed 4-6 weeks after completion of induction chemoradiation<br>* Other names: pneumonectomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mediastinal Nodal Clearance After Completion of Induction Chemoradiotherapy With or Without Panitumumab. | The assessment of whether mediastinal nodes which were involved at the time of study registration were clear of disease following induction chemoradiotherapy with or without panitumumab; the assessment is made at the time of surgery 4-6 weeks after chemoradiation. If surgery could not be performed, the patient was considered as not having had mediastinal nodal clearance. | From date of randomization to time of protocol surgery, approximately 12 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Survival time was calculated from the date of randomization to the date of death from any cause or the date of last follow-up. The Kaplan-Meier method was used to estimate the overall survival rates. One-year survival rates were estimated, not compared. | Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study | 
| Patterns of First Failure | The first failure site will be tabulated, not compared. | Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study. | 
| Percentage of Patients With Grade 3 or Higher Acute and Late Adverse Events | Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Does not include surgical morbidities. An acute adverse event is defined as any grade 3 or worse toxicity occurring during protocol treatment and within 30 days from the end of protocol treatment that is possibly, probably, or definitely related to treatment. Acute adverse events are any adverse events occurring within 30 days of the end of all protocol treatment. Late adverse events are any adverse events occurring after 30 days after the end of all protocol treatment. | Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study. | 
| Surgical Morbidities in Patients With Resectable Disease at Reassessment | A surgical morbidity is any toxicity occurring within 30 days of protocol surgery, as evaluated using CTCAE v4.0. Rates of grade 3 and higher surgical morbidity were calculated; the rates across arms were not compared. | From date of surgery to 30 days following surgery. | 
| Ability of FDG-PET/CT Scan Data to Predict Outcome |  | Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study. | 
| Response Rate | Patients are assessed for best response to protocol treatment using the RECIST criteria. The response rate was calculated as the number of patients who have a complete response (CR) or partial response (PR) divided by the total number of analyzable patients at completion of induction chemoradiation +/- panitumumab and prior to anticipated surgery in each arm. Patients without a documented assessment are considered as not having a CR or PR. Rates are not compared across arms. | From date of randomization to time of protocol surgery, approximately 12 weeks. | 

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