Proteomic Profiling in Predicting Response in Patients Receiving Erlotinib for Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Studying samples of tumor tissue, blood, and urine in the laboratory from patients receiving erlotinib may help doctors predict how patients will respond to treatment. PURPOSE: The phase II trial is studying proteomic profiling to see how well it predicts response in patients receiving erlotinib for stage IIIB, stage IV, or recurrent non-small cell lung cancer.

Detailed Description
-----------------
OBJECTIVES: Primary To define a pre-treatment tumor proteomic profile that predicts response, stable disease, or progressive disease in patients with stage IIIB, stage IV, or recurrent non-small cell lung cancer treated with erlotinib hydrochloride. Secondary To test and refine a pre-treatment serum proteomic expression pattern that predicts response to erlotinib hydrochloride and/or carboplatin and paclitaxel after failing treatment with erlotinib hydrochloride. To test and refine tumor proteomic profiles that predict response to carboplatin and paclitaxel after failing treatment with erlotinib hydrochloride. To analyze individual and pattern(s) of erlotinib hydrochloride-induced genomic and proteomic biomarker changes in relation to response or non-response to treatment. To correlate the efficacy and toxicity of erlotinib hydrochloride with expression of EGFR, EGFR pathway, ErbB family, and other related biomarkers. To determine a set of biomarkers to be evaluated in tumor tissue or surrogate tissues prior to treatment with erlotinib hydrochloride to enable patient selection for therapy. To estimate response rate and progression-free and overall survival of patients treated with erlotinib hydrochloride as initial therapy. To characterize the safety profile of erlotinib hydrochloride in these patients. OUTLINE: This is a multicenter study. Patients receive oral erlotinib hydrochloride once daily until disease progression. At the time of disease progression, patients receive standard chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 15-30 minutes on day 1. Patients with non-squamous cell non-small cell lung cancer also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses. Tumor tissue, plasma, serum, and urine samples are collected at baseline for proteomics analysis. After the completion of study treatment, patients are followed every 8 weeks.

Official Title
-----------------
A Feasibility Study Investigating Translational Science in Chemotherapy-Naive Patients With Stage IIIb or IV Non-Small Cell Lung Cancer (NSCLC) Treated With the EGFR-TKI, Erlotinib

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

Intervention / Treatment
-----------------
* Drug: bevacizumab
* Drug: carboplatin
* Drug: erlotinib hydrochloride
* Drug: paclitaxel
* Genetic: gene expression analysis
* Genetic: protein expression analysis
* Genetic: proteomic profiling
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed non-small cell lung cancer (NSCLC), meeting 1 of the following criteria: Stage IIIB (with pleural effusion) or stage IV disease Recurrent disease after prior surgery Measurable or evaluable disease is desirable but not required No untreated symptomatic brain metastases Patients who are neurologically unstable despite radiotherapy for the brain metastases are not eligible No requirement for steroids to control neurological symptoms PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,500/mm³ Hemoglobin ≥ 9 g/dL Platelet count ≥ 100,000/mm³ Creatinine ≤ 2.0 mg/dL Total bilirubin ≤ 1.5 mg/dL Normal hemostasis by history PT/PTT within 0.5 seconds of normal range Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Willing to undergo biopsy procedures No known severe hypersensitivity to erlotinib hydrochloride or any of the excipients of this product No other concurrent malignancies or malignancies diagnosed within the past 5 years, except basal cell carcinoma or cervical cancer in situ No significant cardiac disease, including any of the following: NYHA class III or IV heart disease Uncontrolled dysrhythmia Myocardial infarction within the past 6 months No evidence of clinically active interstitial lung disease Chronic stable radiographic changes that are asymptomatic allowed No evidence of any other severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease) No evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the trial No uncontrolled hypertension Blood pressure must be ≤ 150/90 mmHg on a stable antihypertensive regimen PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 6 months since prior adjuvant chemotherapy No unresolved chronic toxicity > CTC grade 2 from prior anticancer therapy (except alopecia) More than 30 days since prior non-approved or investigational drugs No prior chemotherapy for advanced NSCLC No concurrent phenytoin, carbamazepine, rifampin, barbiturates, or St. John's wort No concurrent administration of other drugs known to inhibit EGFR No other concurrent anti-neoplastic or anti-tumor agents, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy No other concurrent investigational agents Concurrent cardioprotective doses of aspirin, as recommended by the physician, for cardiovascular disease allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 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: Treatment<br>Erlotinib followed by paclitaxel + carboplatin (+ bevacizumab in non-squamous) at the time disease progression. | Drug: bevacizumab<br>* 15 mg/m2 given through a vein for every 3 weeks<br>Drug: carboplatin<br>* AUC = 6 given through a vein on day 1 of each cycle.<br>Drug: erlotinib hydrochloride<br>* 150 mg taken by mouth daily<br>Drug: paclitaxel<br>* 200 mg/m2 given through a vein on day 1 of each cycle.<br>Genetic: gene expression analysis<br>* Blood and tissue collection.<br>Genetic: protein expression analysis<br>* Blood and tissue collection.<br>Genetic: proteomic profiling<br>* Blood and tissue collection.<br>Other: laboratory biomarker analysis<br>* Blood and tissue collection.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-treatment Tumor Proteomic Profile as a Predictor of Response, Stable Disease, or Progressive Disease |  | End of treatment date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-treatment Serum Proteomic Expression Pattern as a Predictor of Response to Erlotinib Hydrochloride and/or Carboplatin and Paclitaxel After Failing Treatment With Erlotinib Hydrochloride |  | End of treatment date | 
| Tumor Proteomic Profiles as Predictors of Response to Carboplatin and Paclitaxel After Failing Treatment With Erlotinib Hydrochloride |  | End of treatment date | 
| Analysis of Individual and Pattern(s) of Erlotinib Hydrochloride-induced Genomic and Proteomic Biomarker Changes in Relation to Response or Non-response to Treatment | End of treatment date | End of treatment date | 
| Correlation of the Efficacy and Toxicity of Erlotinib Hydrochloride With Expression of EGFR, EGFR Pathway, ErbB Family, and Other Related Biomarkers |  | End of treatment date | 
| Determination of a Set of Biomarkers to be Evaluated in Tumor Tissue or Surrogate Tissues Prior to Treatment With Erlotinib Hydrochloride to Enable Patient Selection for Therapy |  | End of treatment date | 
| Response Rate for Erlotinib Initial Therapy in Chemotherapy-naïve Patients With Advanced NSCLC | Number of patients in each response category, per RECIST v1.1, summarized as follows for target lesion criteria (see RECIST v1.1 for additional details): complete response (CR),disappearance of target lesions; partial response (PR), >=30% decrease in sum of longest diameter of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or SD. The response rate is calculated as the percentage of PR+CR among patients assessed for response. | Through study completion, an average of 1 year | 
| Progression-free Survival (PFS) for Erlotinib Initial Therapy in Chemotherapy-naïve Patients With Advanced NSCLC | PFS is defined as the time from on erlotinib treatment date to progression or death (whichever comes first) before cross-over to PC or PC+B. For those did not progressed nor died, they were censored at the last follow up (either the off erlotinib treatment date or lost follow up date). The median survival time and 95% confidence interval were estimated using Kaplan-meier method. | Through study completion, an average of 1 year | 
| Number of Patients With Worst-grade Toxicities Per Grade | The intensity of the AE will be graded according to the Common Toxicity Criteria (CTC) of the (US) National Cancer Institute (NCI) - Cancer Therapy Evaluation Program (CTEP) [version 3.0 of December 2003] (Appendix B). 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 | Through study completion, an average of 1 year | 
| Overall Survival for Erlotinib Initial Therapy in Chemotherapy-naïve Patients With Advanced NSCLC | The overall survival time is defined as the time from on treatment to death. Patients were censored of they were alive at the last follow up date. The median survival time and its confidence interval were estimated using Kaplan-meier method. | Through study completion, an average of 1 year | 

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