Pemetrexed Disodium or Erlotinib Hydrochloride as Second-Line Therapy in Treating Patients With Advanced Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies pemetrexed disodium to see how well it works compared with erlotinib hydrochloride as second-line therapy in treating patients with non-small cell lung cancer that has spread to other places in the body. Pemetrexed disodium and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed disodium is more effective than erlotinib hydrochloride in treating advanced non-small cell lung cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate whether there are differences in progression-free survival due to treatment with erlotinib (erlotinib hydrochloride) compared to pemetrexed (pemetrexed disodium) for subsets of previously treated non-small cell lung cancer (NSCLC) patients defined by epidermal growth factor receptor (EGFR)-fluorescent in situ hybridization (FISH) positive versus negativity. SECONDARY OBJECTIVES: I. Ascertain the presence or absence of true differences due to treatment in the objective clinical endpoints of overall survival, confirmed response rate, and adverse event profile for subsets of patients defined on the basis of the epidermal growth factor receptor (EGFR)-FISH positivity versus negativity. II. Ascertain the presence or absence of true differences due to treatment in objective clinical endpoints (i.e., progression free survival, overall survival, confirmed response rate, and adverse event profile) for subsets of patients defined on the basis of the epidermal growth factor receptor (EGFR) expression as measured by immunohistochemistry (IHC). III. Ascertain the presence or absence of true differences due to treatment in objective clinical endpoints (i.e., progression free survival, overall survival, confirmed response rate, and adverse event profile) for subsets of patients defined on the basis of the epidermal growth factor receptor (EGFR) gene mutation status (MUT). IV. To evaluate the prognostic effect of EGFR copy number as measured by FISH separately by treatment arm, i.e., is there a difference in outcome for FISH(+) patients receiving erlotinib compared to FISH (-) patients receiving erlotinib, and similarly is there a difference in outcome for FISH(+) patients receiving pemetrexed compared to FISH (-) patients receiving pemetrexed. V. To evaluate the prognostic effect of EGFR expression as measured by IHC separately by treatment arm, i.e., is there a difference in outcome for IHC(+) patients receiving erlotinib compared to IHC (-) patients receiving erlotinib, and similarly is there a difference in outcome for IHC(+) patients receiving pemetrexed compared to IHC (-)patients receiving pemetrexed. VI. To evaluate the prognostic effect of EGFR mutation status separately by treatment arm, i.e., is there a difference in outcome for MUT(+) patients receiving erlotinib compared to MUT(-) patients receiving erlotinib, and similarly is there a difference in outcome for MUT(+) patients receiving pemetrexed compared to MUT(-) patients receiving pemetrexed. VII. To prospectively test the hypothesis that functionally relevant polymorphisms in the genes encoding for pemetrexed targets, as well as genes encoding for one or more of the key enzymes involved in the transport, activation, and inactivation of pemetrexed, either singly or in combination, play a role in the efficacy and/or toxicity of pemetrexed. VIII. To prospectively test the hypothesis that functionally relevant polymorphisms in the EGFR gene as well as genes encoding for one or more of the key enzymes involved in the metabolism of erlotinib, either singly or in combination, play a role in the efficacy and/or toxicity of erlotinib. IX. Evaluate proteomic signatures in blood samples as predictors of survival and response to treatment with erlotinib. X. To evaluate expression of thymidylate synthase, dihydrofolate reductase, phosphoribosylglycineamide (GAR) formyltransferase, and methylthioadenosine phosphorylase gene expression in tumor samples, as measured by IHC or quantitative polymerase chain reaction, as predictors of survival and response to treatment with pemetrexed. XI. To evaluate proteomic signatures in blood samples of patients as predictors of response and survival to treatment with erlotinib. XII. To evaluate the following variables measured in tumor samples, as predictors of response and survival to treatment with pemetrexed: Expression of thymidylate synthase, dihydrofolate reductase and GAR formyltransferase genes methylthioadenosine phosphorylase expression by IHC or quantitative polymerase chain reaction (PCR). XIII. To evaluate the following variables measured in tumor samples, as predictors of response and survival to treatment with erlotinib: Rat sarcoma (Ras) mutational status, EGFR mutational status and, epithelial to mesenchymal transition (EMT) status (measured by E-cadherin expression and vimentin expression) by IHC. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive pemetrexed disodium intravenously (IV) over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.

Official Title
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MARVEL: Marker Validation of Erlotinib in Lung Cancer- A Phase III Biomarker Validation Study of Second-Line Therapy in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Randomized to Pemetrexed Versus Erlotinib

Conditions
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Recurrent Non-Small Cell Lung Carcinoma, Stage IIIA 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: Pemetrexed Disodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented recurrence or disease progression of NSCLC NSCLC must be confirmed by pathologic examination, either on initial diagnosis or disease recurrence/progression; mixed histology allowed if all components consistent with NSCLC Measurable disease, defined as at least one lesion whose longest diameter can be accurately measured as >= 2.0 cm by conventional techniques or as >= 1.0 cm by spiral computed tomography (CT); if spiral CT is used, it must be used for both pre- and post- treatment tumor assessments Prior radiation therapy is permitted as long as: Recovered from the toxic effects of radiation treatment before study entry, except for alopecia =< 25% of bone marrow radiated Presence of measurable disease whether in-field disease progression/recurrence or disease outside the treatment fields of radiation port Absolute neutrophil count (ANC) >= 1,500 uL Platelet (PLT) >= 100,000 uL Hemoglobin (Hgb) >= 10 g/dL Total bilirubin: within normal institutional limits (WNL) OR direct bilirubin =< upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN International normalized ratio (INR) =< 1.5 Calculated creatinine clearance >= 45 mL/min using the Cockcroft-Gault formula Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Negative pregnancy test done =< 7 days prior to pre-registration, for women of childbearing potential only Ability to provide informed consent Life expectancy >= 12 weeks Tissue available and willing to submit tissue for central pathology review and EGFR evaluation; performed on original diagnostic/recurrent tissue (preferably paraffin-embedded tissue blocks); if institution unable to release tissue blocks, willing to submit 25 unstained slides (15 sections cut at 5 microns mounted on charged slides and 10 sections cut at 10 microns mounted on uncharged slides) Must be previously treated for advanced disease with only 1 chemotherapy regimen which must contain cytotoxic agent(s); adjuvant/neoadjuvant treatment with cytotoxic agent(s) administered < 12 months (from date chemotherapy was started) prior to pre-registration will be considered as one prior treatment; NOTE: adjuvant/neoadjuvant treatment administered >= 12 months, use of targeted agents such as monoclonal antibodies prior to pre-registration will NOT be counted as one prior treatment; patient could have had adjuvant/neoadjuvant chemotherapy >= 12 months and 1 systemic chemotherapy regimen for metastatic or recurrent disease Able to take folic acid, vitamin B12 supplementation, and dexamethasone Able to permanently discontinue aspirin dose of >= 1.3 grams/day >= 10 days before and after pemetrexed treatment Fertile patients must use effective contraception Able to take folic acid, vitamin B_12 supplementation, and dexamethasone Stable brain metastasis that have been treated with either whole brain radiation therapy or gamma knife surgery and are off steroid treatment for > 14 days prior to pre-registration, if applicable Willingness to return to enrolling institution for treatment and follow-up Exclusion Criteria: Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Any clinically significant infection, at the treating physician's discretion Known human immunodeficiency virus (HIV) positive patients Impairment of gastrointestinal (GI) function, inability to swallow pills in the absence of a feeding tube, or GI disease that may significantly alter absorption of oral medications (e.g. ulcerative disease, uncontrolled nausea and vomiting, malabsorption syndromes, bowel obstruction, etc) Serious condition that, in the opinion of the investigator, would compromise the patient's ability to complete the study or increase the risk for serious adverse events Any of the following prior therapies: Prior radiation to > 25% of bone marrow EGFR tyrosine kinase inhibitors Pemetrexed Chemotherapy =< 3 weeks prior to pre-registration Mitomycin C/nitrosoureas =< 6 weeks prior to pre-registration Immunotherapy =< 2 weeks prior to pre-registration Biologic therapy =< 2 weeks prior to pre-registration Gene therapy =< 2 weeks prior to pre-registration Full field radiation therapy =< 4 weeks prior to pre-registration Limited field radiation therapy =< 2 weeks prior to pre-registration Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury =< 4 weeks prior to pre-registration or anticipation of need for major surgical procedure during the course of the study; minor surgery =< 2 weeks prior to pre-registration; insertion of a vascular access device is not considered major or minor surgery in this regard Other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) =< 4 weeks prior to pre-registration Steroid therapy for brain metastasis =< 14 days prior to pre-registration Symptomatic serosal effusion (>= Common Terminology Criteria for Adverse Events [CTCAE] v3.0 grade 2 dyspnea) that is not amenable to drainage prior to pre-registration Other invasive solid or hematologic malignancy; exceptions: prior malignancy was diagnosed and definitively treated >= 5 years previously with no subsequent evidence of recurrence; patients with a history of low-grade (Gleason score =< 6) localized prostate cancer will be eligible even if diagnosed < 3 years prior to pre-registration; these patients may continue on medications concomitantly to maintain their disease remission as necessary; patients with carcinoma in situ, regardless of organ involvement, or non-melanoma cutaneous carcinomas are eligible if these were definitively treated >= 3 years previously with no subsequent evidence of recurrence; Note: patients with breast cancer that was definitively treated > 5 years earlier but continue to receive aromatase inhibitors are NOT eligible Only non-measurable disease, defined as all other lesions, including small lesions whose longest diameter measures < 2 cm with conventional techniques or < 1.0 cm with spiral CT, and truly non-measurable lesions, which include the following as per Response Evaluation Criteria In Solid Tumors (RECIST) criteria dated June 1999: Bone lesions Leptomeningeal disease Ascites Pleural/pericardial effusion Inflammatory breast disease Lymphangitis cutis/pulmonis Abdominal masses that are not confirmed and followed by imaging techniques Cystic lesions Single disease site in prior radiation field Any of the following concurrent severe and/or uncontrolled medical conditions: Angina pectoris History of congestive heart failure =< 3 months prior to pre-registration, unless ejection fraction > 40% Myocardial infarction =< 6 months prior to pre-registration Cardiac arrhythmia Diabetes mellitus Hypertension Any other severe underlying diseases which are, in the judgment of the investigator, inappropriate for entry into this study Respiratory symptoms > CTCAE grade 1

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: Arm I (erlotinib hydrochloride)<br>Patients receive erlotinib hydrochloride PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Erlotinib Hydrochloride<br>* Given PO<br>* Other names: Tarceva;|
| Experimental: Arm II (pemetrexed disodium)<br>Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Pemetrexed Disodium<br>* Given IV<br>* Other names: N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Estimated using the method of Kaplan-Meier survival curves to compare PFS between the erlotinib and pemetrexed arms using an intent-to-treat (ITT) analysis. Due to the small sample size (21 of the required 954 patients  2%), analyses within the FISH(+) and FISH(-) groups were not performed, and no formal analyses for the primary or the secondary efficacy outcomes were performed. | Time from randomization to the first date of documented disease progression or death, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure | The distribution of all time to event data will be estimated using the method of Kaplan-Meier survival curves. | The time from date of randomization to the date at which the patient is removed from the treatment, assessed up to 5 years | 
| Overall Survival | Will be estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors except FISH status and cooperative group] will be used to compare overall survival between the erlotinib and pemetrexed arms within the FISH(+) and FISH(-) subgroups, compare overall and progression free survival between the erlotinib and pemetrexed arms within the subgroups defined on the basis of the epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC), and EGFR gene mutation status (MUT). Cox proportional hazards model will be used to assess potential differences. | Time from randomization to time of death from any cause, assessed up to 5 years | 
| Confirmed Response Rate Defined as Complete Response (CR) or a Partial Response (PR) Per Response Evaluation Criteria In Solid Tumors (RECIST) | Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. The proportion of patients with confirmed CR and PR will be computed within each treatment arm and exact binomial confidence intervals for the true proportion computed. Chi-square test and Fisher's exact test will be used to compare the response rates between the treatment arms within the subgroups defined by FISH status, IHC, and MUT. | Up to 5 years |