Erlotinib and Radiation Therapy Plus Combination Chemotherapy in Treating Patients With Inoperable Stage III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining erlotinib and radiation therapy with combination chemotherapy may kill more tumor cells. Phase I trial to study the effectiveness of combining erlotinib and radiation therapy with combination chemotherapy in treating patients who have inoperable stage III non-small cell lung cancer

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of erlotinib that can be administered with chest radiotherapy in combination with cisplatin and etoposide or carboplatin and paclitaxel in patients with inoperable stage III non-small cell lung cancer. II. Determine the dose-limiting toxicity of these regimens in these patients. III. Assess the clinical response (complete response, partial response, progressive disease, or stable disease) in patients treated with these regimens. IV. Determine levels of tumor epidermal growth factor expression in patients treated with these regimens. OUTLINE: This is a multicenter, dose-escalation study of erlotinib. Patients are assigned to 1 of 2 treatment groups. GROUP 1: Patients receive cisplatin IV over 2 hours on days 1, 8, 29, and 36; etoposide IV over 1 hour on days 1-5 and 29-33; and oral erlotinib once daily on days 1-49. Patients undergo concurrent radiotherapy 5 days a week for 7 weeks beginning on day 1. Patients receive consolidation therapy comprising docetaxel IV over 1 hour on days 50, 71, and 92. Some patients may also receive oral erlotinib once daily on days 50-112. GROUP 2: Patients receive induction chemotherapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21. Patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 43, 50, 57, 64, 71, 78, and 85 and oral erlotinib once daily on days 43-91. Patients undergo radiotherapy concurrently with consolidation therapy 5 days a week for 7 weeks beginning on day 43. In both groups, cohorts of 3-6 patients receive escalating doses of erlotinib during concurrent chemoradiotherapy until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which at least 2 of 6 patients experience dose-limiting toxicity. At least 12 patients from each group are treated at the MTD. Patients are followed at 8 weeks. PROJECTED ACCRUAL: A total of 24-48 patients (12-24 per treatment group) will be accrued for this study within 6-12 months.

Official Title
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A Phase I Study Of OSI-774 (NSC #718781)-Based Multimodality Therapy For Inoperable Stage III Non Small Cell Lung Cancer

Conditions
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Adenocarcinoma of the Lung, Bronchoalveolar Cell Lung Cancer, Large Cell Lung Cancer, Squamous Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: etoposide
* Drug: erlotinib hydrochloride
* Radiation: radiation therapy
* Drug: docetaxel
* Drug: paclitaxel
* Drug: carboplatin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-small cell lung cancer Squamous cell carcinoma Adenocarcinoma (including bronchoalveolar) Large cell carcinoma (including giant and clear cell carcinomas) Stage IIIA (T1 or T2, N2) or IIIB disease not amenable to resection or surgery T3, N2 or T4, N0-N2 disease also allowed if based on the closeness to the carina, invasion of the mediastinum, or invasion of the chest wall T3, N0-N1 disease allowed provided the disease is not amenable for surgical resection No M1 disease No disease invasion of a vertebral body Tumors adjacent to a vertebral body allowed provided all gross disease can be encompassed in the radiotherapy boost field and there is no bone invasion Contralateral mediastinal disease (N3) allowed if all gross disease can be encompassed in the radiotherapy boost field Pleural effusion that is transudative, cytologically negative, and non-bloody allowed if the tumor can be encompassed in a reasonable field of radiotherapy No exudative, bloody, or cytologically malignant effusions Effusions present on CT scans but not on chest x-ray (CXR) and too small for thoracentesis are allowed Measurable or evaluable disease Pleural effusions are not considered measurable or evaluable Measurable disease is defined as any mass in 2 perpendicular diameters by CXR, CT scan, or MRI Evaluable disease includes lesions apparent on CXR or CT scan that are: Ill-defined masses associated with post-obstructive changes Mediastinal or hilar adenopathy measurable in only one dimension Performance status - ECOG 0-1 Performance status - Karnofsky 70-100% More than 6 months WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin normal AST and ALT no greater than 1.5 times upper limit of normal (ULN) and alkaline phosphatase normal AST and ALT normal and alkaline phosphatase no greater than 2.5 times ULN Creatinine normal Creatinine clearance at least 50 mL/min No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia No history of cornea abnormalities (e.g., dry-eye syndrome, Sjögren's syndrome) No congenital abnormality (e.g., Fuch's dystrophy) No abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose) No abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production test) No gastrointestinal tract disease resulting in the inability to take oral medications No required IV alimentation No peptic ulcer disease Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of allergy to compounds of similar chemical or biologic composition to erlotinib or other study agents No significant traumatic injury within the past 21 days No other uncontrolled concurrent illness No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other active malignancy within the past 6 months except non-melanoma skin cancer No concurrent colony-stimulating factors (filgrastim [G-CSF] or sargramostim [GM-CSF]) with radiotherapy No prior chemotherapy for lung cancer See Disease Characteristics No prior chest radiotherapy See Disease Characteristics At least 7 days since prior mediastinoscopy More than 3 weeks since prior formal exploratory thoracotomy More than 3 weeks since prior major surgery No prior surgical procedures affecting absorption No prior epidermal growth factor receptor-targeting therapies No other concurrent investigational or commercial agents or therapies directed at malignancy No concurrent combination antiretroviral therapy for HIV-positive patients

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (cisplatin, etoposide, erlotinib, and docetaxel)<br>Patients receive cisplatin IV over 2 hours on days 1, 8, 29, and 36; etoposide IV over 1 hour on days 1-5 and 29-33; and oral erlotinib once daily on days 1-49. Patients undergo concurrent radiotherapy 5 days a week for 7 weeks beginning on day 1. Patients receive consolidation therapy comprising docetaxel IV over 1 hour on days 50, 71, and 92. Some patients may also receive oral erlotinib once daily on days 50-112. | Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: OSI-774;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Drug: docetaxel<br>* Given IV<br>* Other names: TXT;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group II (paclitaxel, carboplatin, and erlotinib<br>Patients receive induction chemotherapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21. Patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 43, 50, 57, 64, 71, 78, and 85 and oral erlotinib once daily on days 43-91. Patients undergo radiotherapy concurrently with consolidation therapy 5 days a week for 7 weeks beginning on day 43. | Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: OSI-774;Radiation: radiation therapy<br>* Undergo radiotherapy<br>* Other names: therapy, radiation;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the dose at which at least 2 of 6 patients experience dose-limiting toxicity assessed using NCI CTCAE version 3.0 |  | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response assessed using RECIST |  | Up to 8 weeks | 
| Level of EGFR expression |  | Up to 8 weeks |