Erlotinib Hydrochloride With or Without Celecoxib in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Erlotinib hydrochloride and celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Celecoxib may also stop the growth of lung cancer by blocking blood flow to the tumor. Giving erlotinib hydrochloride together with celecoxib may kill more tumor cells. PURPOSE: This randomized phase II trial is studying how well giving erlotinib hydrochloride together with celecoxib works compared with erlotinib hydrochloride alone in treating patients with stage IIIB-IV non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Comparison of progression-free survival (PFS) in patients receiving erlotinib + celecoxib vs. erlotinib + placebo for advanced NSCLC. SECONDARY OBJECTIVES: I. Objective tumor response rate as defined by RECIST Criteria for subjects receiving erlotinib/celecoxib treatment arms. II. Categorize the change in e-cadherin expression from baseline to week 8 in a subset of subjects. III. Evaluation of overall survival (OS). IV. Measurement of COX-2, EGFR by immunohistochemistry and EGFR amplification by FISH, and EGFR mutation status to correlate with clinical response. V. Measurement of change in urinary PGE-M and correlation with response. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral erlotinib hydrochloride once daily and oral placebo twice daily on days 1-28. ARM II: Patients receive oral erlotinib hydrochloride once daily and oral celecoxib twice daily on days 1-28. In both arms, treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Official Title
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A Randomized, Placebo-Controlled Phase II Clinical Trial of Combination Erlotinib (Tarceva) and Celecoxib (Celebrex) Versus Erlotinib (Tarceva)/Placebo in Advanced Non-Small Cell Lung Cancer Patients

Conditions
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Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: celecoxib
* Other: placebo
* Other: laboratory biomarker analysis
* Other: immunohistochemistry staining method
* Genetic: fluorescence in situ hybridization
* Genetic: mutation analysis
* Genetic: protein expression analysis
* Genetic: gene expression analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Pathologically proven NSCLC, stage IIIB (defined as: with pleural effusion or recurrence after mediastinal radiation and chemotherapy) or IV Available tumor tissue for mutation screening Measurable stage IIIb or IV disease by RECIST guidelines ECOG performance status of 0 or 1 Progressive disease despite >= 1 prior chemotherapy regimens as standard of care or subject's refusal or inability to receive standard chemotherapy Normal renal function (defined as serum creatinine =< 2mg/dl) Normal liver function (defined as serum total bilirubin =< 1.5, and serum transaminases =< 2.5X the upper limits of normal [ULN]); if liver metastases are present, serum transaminases > 5X the ULN No evidence of coagulopathy (defined as PT and/or PTT =< 1.5X ULN or platelets >= 100,000) No evidence of leukopenia (defined as absolute neutrophil count >= 1,500 mm^3) Negative pregnancy test prior to initiation of treatment and adequate contraception throughout treatment Exclusion Cytotoxic chemotherapy agents within 4 weeks of initiating treatment; all toxicities must be recovered to baseline or NCI CTCAE v3.0 Grade 1 from all acute effects of prior cancer treatment, except alopecia or any clinically insignificant effect, prior to study initiation Evidence of NYHA class III or greater cardiac disease, history of myocardial infarction, cerebral vascular accident, symptomatic ventricular arrhythmia, or symptomatic conduction abnormality Non-cytoxic therapy within 2 weeks of initiating treatment ; all toxicities must be recovered to baseline or NCI CTCAE v3.0 Grade 1 from all acute effects of prior cancer treatment, except alopecia or any clinically insignificant effect, prior to study initiation Prior radiotherapy to target lesions is not permitted unless completed more than 4 weeks prior to treatment within the study and that there has been documented progression at these sites (Radiotherapy to non-target lesions is permitted within 2 weeks of study entry provided all acute effects of the radiotherapy have resolved at least grade 1) Comorbid disease or a medical condition that would impair the ability of the subject to receive or comply with the study protocol Prior malignancy within the last 3 years with the exception of non-melanoma skin cancer or cervical cancer in situ Hypersensitivity of erlotinib or celecoxib or to any of the excipients of these products Hypersensitivity to sulfonamides, aspirin or other NSAIDS Prior history of EGFR inhibitor for the treatment of cancer Previous history of gastrointestinal ulceration, bleeding or perforation Concurrent use of COX-2 inhibitors or other NSAIDS (For subjects on NSAIDS prior to study initiation, cessation of the drug for 72 hours prior to study entry is required) Chronic or concurrent use of steroids (topical steroids are acceptable if medically indicated) Subjects who require treatment with fluconazole or lithium Any evidence of clinically active interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) Renal insufficiency (defined as serum creatinine > 2 mg/dl) Liver insufficiency (defined as serum total bilirubin > 1.5, or serum transaminases > 2.5C the upper limits of normal [ULN]); if liver metastases are present, serum transaminases > 5X the ULN Coagulopathy (defined as PT and/or PTT > 1.5X ULN or platelets < 100,000) Leukopenia (defined as absolute neutrophil count < 1,500/mm^3) Pregnancy or inadequate contraception Lactating females Active CNS metastasis (stable, treated CNS metastasis acceptable)

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive oral erlotinib hydrochloride once daily and oral placebo twice daily on days 1-28. | Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: Tarceva;Other: placebo<br>* Given orally<br>* Other names: PLCB;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Genetic: fluorescence in situ hybridization<br>* Correlative studies<br>* Other names: fluorescence in situ hybridization (FISH);Genetic: mutation analysis<br>* Correlative studies<br>Genetic: protein expression analysis<br>* Correlative studies<br>Genetic: gene expression analysis<br>* Correlative studies<br>|
| Experimental: Arm II<br>Patients receive oral erlotinib hydrochloride once daily and oral celecoxib twice daily on days 1-28. | Drug: erlotinib hydrochloride<br>* Given orally<br>* Other names: Tarceva;Drug: celecoxib<br>* Given orally<br>* Other names: YM 177;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Genetic: fluorescence in situ hybridization<br>* Correlative studies<br>* Other names: fluorescence in situ hybridization (FISH);Genetic: mutation analysis<br>* Correlative studies<br>Genetic: protein expression analysis<br>* Correlative studies<br>Genetic: gene expression analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. | Until disease progression, up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | 16 weeks post start of treatment | 
| Progression-free Survival - Elevated PGEM | Estimated using the product-limit method of Kaplan and Meier.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. | Until disease progression, up to 5 years. | 
| Progression-free Survival - EGRF | Estimated using the product-limit method of Kaplan and Meier.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. | Until disease progression, up to 5 years. | 
| Progression-free Survival - Low PGEM | Estimated using the product-limit method of Kaplan and Meier.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. | Until disease progression, up to 5 years. |