Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. 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. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. SECONDARY OBJECTIVES: I. To evaluate response rate. II. To assess toxicity. III. To assess overall survival. IV. To correlate clinical outcomes with tumor molecular aberrations identified from deep sequencing of selected kinomes in patients from whom adequate baseline tissue is available. OUTLINE: Eligible patients are assigned to one of two cohorts based on pre-enrollment screening by the enrolling institution for two biomarkers: EGFR TK mutation and EML4-ALK fusion arrangement. Within each cohort, patients are randomized to either an experimental or control arm, resulting in a total of four treatment arms overall. Patients with both the EGFR mutation and ALK arrangement are placed in the ALK Cohort. Planned Sample Size: 156 for the EGFR mutation cohort and 78 for the ALK translocation cohort After completion of study treatment, patients are followed at 1 and 2 months, 4-6 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Official Title
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A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non-small Cell Lung Cancer (NSCLC)

Conditions
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Stage III Non-Small Cell Lung Cancer AJCC v7, Stage IIIA Non-Small Cell Lung Cancer AJCC v7, Stage IIIB Non-Small Cell Lung Cancer AJCC v7

Intervention / Treatment
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* Radiation: Radiation Therapy
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Crizotinib
* Drug: Erlotinib
* Drug: Etoposide
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known sensitive mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration Zubrod performance status 0-1 within 14 days prior to registration Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 Platelets >= 100,000 cells/mm^3 Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration Bilirubin within normal institutional limits within 14 days prior to registration Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Atelectasis of the entire lung Contralateral hilar node involvement Exudative, bloody, or cytologically malignant effusions Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception Prior allergic reaction to the study drug(s) involved in this protocol

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 |
| --- | --- |
| Experimental: EGFR: Erlotinib<br>Induction erlotinib for 12 weeks followed by chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. Patients who have had no response (partial or complete) after 6 weeks of induction therapy start chemoradiation therapy immediately. | Radiation: Radiation Therapy<br>* 30 once-daily 2 Gy fractions over 6 weeks totaling 60 Gy of intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT).<br>* Other names: Intensity-modulated radiation therapy;Drug: Carboplatin<br>* Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, AUC=6, IV, days 1 and 22.<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* 50 mg/m2, IV (intravenous), on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, cisplatin will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: Platosin;Drug: Erlotinib<br>* 150 mg, orally, once daily for four 3-week cycles (12 weeks in total)<br>* Other names: Tarceva;Drug: Etoposide<br>* 50 mg/m2, IV, on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, etoposide will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: VP-16-213;Drug: Paclitaxel<br>* Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.<br>* Other names: Taxol Konzentrat;|
| Active Comparator: EGFR: No Erlotinib<br>Chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. | Radiation: Radiation Therapy<br>* 30 once-daily 2 Gy fractions over 6 weeks totaling 60 Gy of intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT).<br>* Other names: Intensity-modulated radiation therapy;Drug: Carboplatin<br>* Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, AUC=6, IV, days 1 and 22.<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* 50 mg/m2, IV (intravenous), on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, cisplatin will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: Platosin;Drug: Etoposide<br>* 50 mg/m2, IV, on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, etoposide will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: VP-16-213;Drug: Paclitaxel<br>* Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.<br>* Other names: Taxol Konzentrat;|
| Experimental: ALK: Crizotinib<br>Induction crizotinib for 12 weeks followed by chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. Patients who have had no response (partial or complete) after 6 weeks of induction therapy start chemoradiation therapy immediately. | Radiation: Radiation Therapy<br>* 30 once-daily 2 Gy fractions over 6 weeks totaling 60 Gy of intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT).<br>* Other names: Intensity-modulated radiation therapy;Drug: Carboplatin<br>* Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, AUC=6, IV, days 1 and 22.<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* 50 mg/m2, IV (intravenous), on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, cisplatin will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: Platosin;Drug: Crizotinib<br>* 250 mg, orally, twice daily for four 3-week cycles (12 weeks in total)<br>* Other names: Xalkori;Drug: Etoposide<br>* 50 mg/m2, IV, on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, etoposide will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: VP-16-213;Drug: Paclitaxel<br>* Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.<br>* Other names: Taxol Konzentrat;|
| Active Comparator: ALK: No Crizotinib<br>Chemotherapy (either cisplatin/etoposide or paclitaxel/carboplatin) and radiation therapy. | Radiation: Radiation Therapy<br>* 30 once-daily 2 Gy fractions over 6 weeks totaling 60 Gy of intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT).<br>* Other names: Intensity-modulated radiation therapy;Drug: Carboplatin<br>* Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, AUC=6, IV, days 1 and 22.<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* 50 mg/m2, IV (intravenous), on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, cisplatin will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: Platosin;Drug: Etoposide<br>* 50 mg/m2, IV, on days 1 and 8 of two 4-week cycles concurrent with radiation therapy. For patients receiving either erlotinib or crizotinib, etoposide will begin 2 weeks after the completion of erlotinib or crizotinib, as applicable.<br>* Other names: VP-16-213;Drug: Paclitaxel<br>* Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. For patients receiving either erlotinib or crizotinib, carboplatin will begin 2 weeks after erlotinib or crizotinib, as applicable. Consolidation: 4-6 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.<br>* Other names: Taxol Konzentrat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression-free survival time is measured from the date of randomization to the date of first progression, death, or last known follow-up (censored). No statistical testing was done due to early study termination. | From randomization to study termination. Maximum follow-up was 39.0 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Complete or Partial Response | Per the RECIST guideline v1.1 complete response is defined as the disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. No statistical testing was done due to early study termination. | From randomization to study termination. Maximum follow-up was 39.0 months | 
| Number of Patients With Grade 3-5 Adverse Events | Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 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. | From randomization to study termination. Maximum follow-up was 39.0 months | 
| Overall Survival | Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. | From randomization to study termination. Maximum follow-up was 39.0 months | 
| Local-regional Progression-free Survival | Progression is defined using the RECIST guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new regional lesions. Local progression is defined as progression within the planning target volume (PTV). Regional progression is defined as progression outside of the PTV but within the same lobe of the lung as the primary tumor or in regional lymph nodes as defined by the American Joint Committee on Cancer (AJCC) 7th edition nodal stations. Local-regional progression-free survival time is measured from the date of randomization to the date of first local-regional progression, death, or last known follow-up (censored). Local-regional progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination. | From randomization to study termination. Maximum follow-up was 39.0 months | 
| Distant Progression-free Survival | Distant progression is defined as the first occurrence of distant metastasis. Distant progression-free survival time is measured from the date of randomization to the date of first distant progression, death, or last known follow-up (censored). Distant progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination. | From randomization to study termination. Maximum follow-up was 39.0 months | 
| Correlation Between Clinical Outcomes and Tumor Molecular Aberrations |  | Baseline |