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

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

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.

Study Overview

• Status: Terminated
• Conditions: Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Erlotinib Hydrochloride; Drug: Pemetrexed Disodium

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Arkansas
    • Fort Smith, Arkansas, United States, 72901
      • Sparks Regional Medical Center
  • California
    • Antioch, California, United States, 94531
      • Kaiser Permanente-Deer Valley Medical Center
    • Fremont, California, United States, 94538
      • Kaiser Permanente-Fremont
    • Marysville, California, United States, 95901
      • Fremont - Rideout Cancer Center
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Pleasanton, California, United States, 94588
      • Valley Care Health System - Pleasanton
    • Redwood City, California, United States, 94063
      • Kaiser Permanente-Redwood City
    • Richmond, California, United States, 94801
      • Kaiser Permanente-Richmond
    • Roseville, California, United States, 95661
      • Kaiser Permanente-Roseville
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • Sacramento, California, United States, 95823
      • Kaiser Permanente-South Sacramento
    • Sacramento, California, United States, 95825
      • Kaiser Permanente - Sacramento
    • San Francisco, California, United States, 94115
      • Kaiser Permanente-San Francisco
    • San Jose, California, United States, 95119
      • Kaiser Permanente-Santa Teresa-San Jose
    • San Leandro, California, United States, 94577
      • Kaiser Permanente San Leandro
    • San Rafael, California, United States, 94903
      • Kaiser Permanente-San Rafael
    • Santa Clara, California, United States, 95051
      • Kaiser Permanente Medical Center - Santa Clara
    • Santa Rosa, California, United States, 95403
      • Kaiser Permanente-Santa Rosa
    • South San Francisco, California, United States, 94080
      • Kaiser Permanente-South San Francisco
    • Stockton, California, United States, 95210
      • Kaiser Permanente-Stockton
    • Truckee, California, United States, 96161
      • Tahoe Forest Cancer Center
    • Vacaville, California, United States, 95688
      • Kaiser Permanente Medical Center-Vacaville
    • Vallejo, California, United States, 94589
      • Kaiser Permanente-Vallejo
    • Walnut Creek, California, United States, 94596
      • Kaiser Permanente-Walnut Creek
  • Colorado
    • Aurora, Colorado, United States, 80012
      • The Medical Center of Aurora
    • Boulder, Colorado, United States, 80301
      • Boulder Community Hospital
    • Colorado Springs, Colorado, United States, 80907
      • Penrose-Saint Francis Healthcare
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80218
      • Presbyterian - Saint Lukes Medical Center - Health One
    • Denver, Colorado, United States, 80220
      • Rose Medical Center
    • Denver, Colorado, United States, 80218
      • Exempla Saint Joseph Hospital
    • Denver, Colorado, United States, 80224-2522
      • Colorado Cancer Research Program CCOP
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
    • Grand Junction, Colorado, United States, 81502
      • Saint Mary's Hospital and Regional Medical Center
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Lakewood, Colorado, United States, 80228
      • Saint Anthony Hospital
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Longmont, Colorado, United States, 80501
      • Longmont United Hospital
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
    • Pueblo, Colorado, United States, 81004
      • Saint Mary Corwin Medical Center
    • Thornton, Colorado, United States, 80229
      • North Suburban Medical Center
    • Wheat Ridge, Colorado, United States, 80033
      • SCL Health Lutheran Medical Center
  • Connecticut
    • Bristol, Connecticut, United States, 06011
      • Bristol Hospital
    • Middletown, Connecticut, United States, 06457
      • Middlesex Hospital
  • Florida
    • Boca Raton, Florida, United States, 33428
      • Lynn Regional Cancer Center - West
    • Boca Raton, Florida, United States, 33486
      • Boca Raton Comprehensive Cancer Center
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Illinois
    • Berwyn, Illinois, United States, 60402
      • MacNeal Hospital and Cancer Center
    • Bloomington, Illinois, United States, 61704
      • Illinois CancerCare-Bloomington
    • Bloomington, Illinois, United States, 61701
      • Saint Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Illinois CancerCare-Canton
    • Canton, Illinois, United States, 61520
      • Graham Hospital Association
    • Carthage, Illinois, United States, 62321
      • Illinois CancerCare-Carthage
    • Carthage, Illinois, United States, 62321
      • Memorial Hospital
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60611
      • Hematology and Oncology Associates
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Eureka, Illinois, United States, 61530
      • Illinois CancerCare-Eureka
    • Eureka, Illinois, United States, 61530
      • Eureka Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Cottage Hospital
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare Galesburg
    • Galesburg, Illinois, United States, 61401
      • Illinois CancerCare-Cottage
    • Havana, Illinois, United States, 62644
      • Mason District Hospital
    • Havana, Illinois, United States, 62644
      • Illinois CancerCare-Havana
    • Highland Park, Illinois, United States, 60035
      • Hematology Oncology Associates of Illinois-Highland Park
    • Hopedale, Illinois, United States, 61747
      • Hopedale Medical Complex - Hospital
    • Joliet, Illinois, United States, 60432
      • Midwest Center for Hematology Oncology
    • Kewanee, Illinois, United States, 61443
      • Illinois CancerCare-Kewanee Clinic
    • Libertyville, Illinois, United States, 60048
      • NorthShore Hematology Oncology-Libertyville
    • Macomb, Illinois, United States, 61455
      • Illinois CancerCare-Macomb
    • Macomb, Illinois, United States, 61455
      • Mcdonough District Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Monmouth, Illinois, United States, 61462
      • Illinois CancerCare-Monmouth
    • Monmouth, Illinois, United States, 61462
      • Holy Family Medical Center
    • Naperville, Illinois, United States, 60563
      • DuPage Medical Group-Ogden
    • Niles, Illinois, United States, 60714
      • Illinois Cancer Specialists-Niles
    • Normal, Illinois, United States, 61761
      • Community Cancer Center Foundation
    • Normal, Illinois, United States, 61761
      • Bromenn Regional Medical Center
    • Normal, Illinois, United States, 61761
      • Illinois CancerCare-Community Cancer Center
    • Ottawa, Illinois, United States, 61350
      • Illinois CancerCare-Ottawa Clinic
    • Ottawa, Illinois, United States, 61350
      • Ottawa Regional Hospital and Healthcare Center
    • Pekin, Illinois, United States, 61554
      • Illinois CancerCare-Pekin
    • Pekin, Illinois, United States, 61554
      • Pekin Cancer Treatment Center
    • Pekin, Illinois, United States, 61554
      • Pekin Hospital
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peoria, Illinois, United States, 61614
      • Proctor Hospital
    • Peoria, Illinois, United States, 61603
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61615-7827
      • OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC
    • Peoria, Illinois, United States, 61615
      • Illinois Oncology Research Association CCOP
    • Peru, Illinois, United States, 61354
      • Illinois CancerCare-Peru
    • Peru, Illinois, United States, 61354
      • Illinois Valley Hospital
    • Princeton, Illinois, United States, 61356
      • Illinois CancerCare-Princeton
    • Princeton, Illinois, United States, 61356
      • Perry Memorial Hospital
    • Skokie, Illinois, United States, 60076
      • Hematology Oncology Associates of Illinois - Skokie
    • Spring Valley, Illinois, United States, 61362
      • Saint Margaret's Hospital
    • Spring Valley, Illinois, United States, 61362
      • Illinois CancerCare-Spring Valley
    • Springfield, Illinois, United States, 62781
      • Memorial Medical Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Franciscan St. Francis Health-Beech Grove
    • Richmond, Indiana, United States, 47374
      • Reid Hospital and Health Care Services
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic PC-William R Bliss Cancer Center
    • Bettendorf, Iowa, United States, 52722
      • Hematology Oncology Associates-Quad Cities
    • Cedar Rapids, Iowa, United States, 52403
      • Mercy Hospital
    • Cedar Rapids, Iowa, United States, 52403
      • Oncology Associates at Mercy Medical Center
    • Cedar Rapids, Iowa, United States, 52403
      • Cedar Rapids Oncology Association
    • Clive, Iowa, United States, 50325
      • Medical Oncology and Hematology Associates-West Des Moines
    • Davenport, Iowa, United States, 52803
      • Genesis Medical Center - East Campus
    • Davenport, Iowa, United States, 52804
      • Genesis Medical Center - West Campus
    • Des Moines, Iowa, United States, 50309
      • Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Medical Center - Des Moines
    • Des Moines, Iowa, United States, 50309
      • Medical Oncology and Hematology Associates-Des Moines
    • Des Moines, Iowa, United States, 50316
      • Iowa Lutheran Hospital
    • Des Moines, Iowa, United States, 50314
      • Medical Oncology and Hematology Associates-Laurel
    • Des Moines, Iowa, United States, 50307
      • Mercy Capitol
    • Des Moines, Iowa, United States, 50309
      • Iowa Oncology Research Association CCOP
    • Sioux City, Iowa, United States, 51101
      • Siouxland Regional Cancer Center
    • Sioux City, Iowa, United States, 51104
      • Saint Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center-Sioux City
    • Waterloo, Iowa, United States, 50702
      • Covenant Medical Center
  • Kansas
    • Anthony, Kansas, United States, 67003
      • Hospital District Sixth of Harper County
    • Overland Park, Kansas, United States, 66209
      • Menorah Medical Center
    • Overland Park, Kansas, United States, 66213
      • Saint Luke's South Hospital
    • Shawnee Mission, Kansas, United States, 66204
      • Shawnee Mission Medical Center-KCCC
    • Topeka, Kansas, United States, 66604
      • Stormont-Vail Regional Health Center
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center
    • Easton, Maryland, United States, 21601
      • The Memorial Hospital at Easton
    • Rockville, Maryland, United States, 20850-2062
      • Cancer Trials Support Unit
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Brighton, Massachusetts, United States, 02135-2997
      • Steward Saint Elizabeth's Medical Center
    • Hyannis, Massachusetts, United States, 02601
      • Cape Cod Hospital
  • Michigan
    • Adrian, Michigan, United States, 49221
      • Bixby Medical Center
    • Adrian, Michigan, United States, 49221
      • Hickman Cancer Center
    • Ann Arbor, Michigan, United States, 48106-0995
      • Saint Joseph Mercy Hospital
    • Ann Arbor, Michigan, United States, 48106
      • Michigan Cancer Research Consortium CCOP
    • Battle Creek, Michigan, United States, 49017
      • Bronson Battle Creek
    • Big Rapids, Michigan, United States, 49307
      • Spectrum Health Big Rapids Hospital
    • Dearborn, Michigan, United States, 48124
      • Oakwood Hospital and Medical Center
    • Detroit, Michigan, United States, 48236
      • Saint John Hospital and Medical Center
    • Flint, Michigan, United States, 48502
      • Hurley Medical Center
    • Flint, Michigan, United States, 48532
      • Genesys Regional Medical Center-West Flint Campus
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Grand Rapids, Michigan, United States, 49503
      • Mercy Health Saint Mary's
    • Grand Rapids, Michigan, United States, 49503
      • Grand Rapids Clinical Oncology Program
    • Jackson, Michigan, United States, 49201
      • Allegiance Health
    • Lansing, Michigan, United States, 48912
      • Sparrow Hospital
    • Livonia, Michigan, United States, 48154
      • Saint Mary Mercy Hospital
    • Monroe, Michigan, United States, 48162
      • Mercy Memorial Hospital
    • Monroe, Michigan, United States, 48162
      • Toledo Clinic Cancer Centers-Monroe
    • Muskegon, Michigan, United States, 49444
      • Mercy Health Mercy Campus
    • Pontiac, Michigan, United States, 48341
      • Saint Joseph Mercy Oakland
    • Port Huron, Michigan, United States, 48060
      • Saint Joseph Mercy Port Huron
    • Saginaw, Michigan, United States, 48601
      • Saint Mary's of Michigan
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
    • Warren, Michigan, United States, 48093
      • Saint John Macomb-Oakland Hospital
    • Wyoming, Michigan, United States, 49519
      • Metro Health Hospital
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Cancer Center
    • Duluth, Minnesota, United States, 55805
      • Essentia Health Saint Mary's Medical Center
    • Duluth, Minnesota, United States, 55805
      • Miller-Dwan Hospital
    • Hutchinson, Minnesota, United States, 55350
      • Hutchinson Area Health Care
    • Litchfield, Minnesota, United States, 55355
      • Meeker County Memorial Hospital
    • Maplewood, Minnesota, United States, 55109
      • Saint John's Hospital - Healtheast
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute
    • Minneapolis, Minnesota, United States, 55407
      • Minnesota Cooperative Group Outreach Program
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
    • Willmar, Minnesota, United States, 56201
      • Rice Memorial Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64116
      • North Kansas City Hospital
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center
    • Kansas City, Missouri, United States, 64108
      • Truman Medical Center
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Cancer Institute
    • Kansas City, Missouri, United States, 64114
      • Saint Joseph Health Center
    • Lee's Summit, Missouri, United States, 64086
      • Saint Luke's East - Lee's Summit
    • Liberty, Missouri, United States, 64068
      • Liberty Radiation Oncology Center
    • Liberty, Missouri, United States, 64068
      • Liberty Hospital
    • Saint Joseph, Missouri, United States, 64506
      • Heartland Regional Medical Center
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Center for Cancer Care and Research
  • Montana
    • Billings, Montana, United States, 59101
      • Saint Vincent Healthcare
    • Billings, Montana, United States, 59101
      • Northern Rockies Radiation Oncology Center
    • Billings, Montana, United States, 59102
      • Frontier Cancer Center and Blood Institute-Billings
    • Billings, Montana, United States, 59107
      • Billings Clinic Cancer Center
    • Billings, Montana, United States, 59101
      • Montana Cancer Consortium NCORP
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Hospital
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Butte, Montana, United States, 59701
      • Saint James Community Hospital and Cancer Treatment Center
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic
    • Great Falls, Montana, United States, 59405
      • Berdeaux, Donald MD (UIA Investigator)
    • Havre, Montana, United States, 59501
      • Northern Montana Hospital
    • Helena, Montana, United States, 59601
      • Saint Peter's Community Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology
    • Missoula, Montana, United States, 59802
      • Saint Patrick Hospital - Community Hospital
    • Missoula, Montana, United States, 59804
      • Guardian Oncology and Center for Wellness
    • Missoula, Montana, United States, 59801
      • Community Medical Hospital
    • Missoula, Montana, United States, 59802
      • Montana Cancer Specialists
  • Nebraska
    • Kearney, Nebraska, United States, 68847
      • CHI Health Good Samaritan
  • New Jersey
    • East Orange, New Jersey, United States, 07018-1095
      • Veterans Adminstration New Jersey Health Care System
    • Flemington, New Jersey, United States, 08822
      • Hunterdon Medical Center
    • Mount Holly, New Jersey, United States, 08060
      • Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County
    • Red Bank, New Jersey, United States, 07701
      • Riverview Medical Center/Booker Cancer Center
    • Voorhees, New Jersey, United States, 08043
      • Virtua West Jersey Hospital Voorhees
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Syracuse, New York, United States, 13210
      • Syracuse Veterans Administration Medical Center
  • North Carolina
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Hendersonville, North Carolina, United States, 28791
      • Margaret R Pardee Memorial Hospital
    • Rutherfordton, North Carolina, United States, 28139
      • Rutherford Hospital
    • Winston-Salem, North Carolina, United States, 27104
      • Southeast Cancer Consortium-Upstate NCORP
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Sanford Bismarck Medical Center
    • Bismarck, North Dakota, United States, 58501
      • Mid Dakota Clinic
    • Bismarck, North Dakota, United States, 58501
      • Saint Alexius Medical Center
    • Grand Forks, North Dakota, United States, 58201
      • Altru Cancer Center
  • Ohio
    • Bowling Green, Ohio, United States, 43402
      • Toledo Clinic Cancer Centers-Bowling Green
    • Clyde, Ohio, United States, 43410
      • North Coast Cancer Care-Clyde
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital - Dayton
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Samaritan North Health Center
    • Dayton, Ohio, United States, 45405
      • Grandview Hospital
    • Dayton, Ohio, United States, 45420
      • Dayton CCOP
    • Elyria, Ohio, United States, 44035
      • Hematology Oncology Center Incorporated
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Hospital
    • Franklin, Ohio, United States, 45005-1066
      • Atrium Medical Center-Middletown Regional Hospital
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
    • Lima, Ohio, United States, 45804
      • Lima Memorial Hospital
    • Maumee, Ohio, United States, 43537
      • Toledo Clinic Cancer Centers-Maumee
    • Maumee, Ohio, United States, 43537
      • Toledo Radiation Oncology at Northwest Ohio Onocolgy Center
    • Maumee, Ohio, United States, 43537
      • Saint Luke's Hospital
    • Oregon, Ohio, United States, 43616
      • Saint Charles Hospital
    • Oregon, Ohio, United States, 43616
      • Toledo Clinic Cancer Centers-Oregon
    • Sandusky, Ohio, United States, 44870
      • North Coast Cancer Care
    • Sylvania, Ohio, United States, 43560
      • Flower Hospital
    • Tiffin, Ohio, United States, 44883
      • Mercy Hospital of Tiffin
    • Toledo, Ohio, United States, 43608
      • Saint Vincent Mercy Medical Center
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Centers-Toledo
    • Toledo, Ohio, United States, 43614
      • University of Toledo
    • Toledo, Ohio, United States, 43617
      • Toledo Community Hospital Oncology Program CCOP
    • Toledo, Ohio, United States, 43606
      • The Toledo Hospital/Toledo Children's Hospital
    • Toledo, Ohio, United States, 43623
      • Mercy Saint Anne Hospital
    • Troy, Ohio, United States, 45373
      • Upper Valley Medical Center
    • Wauseon, Ohio, United States, 43567
      • Fulton County Health Center
    • Wilmington, Ohio, United States, 45177
      • Clinton Memorial Hospital
    • Xenia, Ohio, United States, 45385
      • Greene Memorial Hospital
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hazleton, Pennsylvania, United States, 18201
      • Geisinger Medical Center-Cancer Center Hazleton
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Scranton, Pennsylvania, United States, 18510
      • Scranton Hematology Oncology
    • Scranton, Pennsylvania, United States, 18501
      • Mercy Hospital
    • State College, Pennsylvania, United States, 16801
      • Geisinger Medical Group
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Geisinger Wyoming Valley/Henry Cancer Center
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health Hospital
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Medical Center
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Regional Medical Center
    • Fredericksburg, Virginia, United States, 22401
      • Fredericksburg Oncology Inc
    • Martinsville, Virginia, United States, 24115
      • Memorial Hospital Of Martinsville
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • Wyoming
    • Casper, Wyoming, United States, 82609
      • Rocky Mountain Oncology
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (erlotinib hydrochloride); 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; Given PO; Other Names: Cp-358,774; Tarceva; OSI-774
Experimental: Arm II (pemetrexed disodium); 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; Given IV; Other Names: Alimta; LY231514; 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?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Eastern Cooperative Oncology Group; NCIC Clinical Trials Group; Southwest Oncology Group; Cancer and Leukemia Group B
• Investigators: Principal Investigator: Alex Adjei, Alliance for Clinical Trials in Oncology

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: August 20, 2008
• First Submitted That Met QC Criteria: August 20, 2008
• First Posted (Estimate): August 21, 2008

Study Record Updates

• Last Update Posted (Estimate): October 29, 2015
• Last Update Submitted That Met QC Criteria: October 6, 2015
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Folic Acid Antagonists; Erlotinib Hydrochloride; Pemetrexed
• Other Study ID Numbers: NCI-2009-00663 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); U10CA025224 (U.S. NIH Grant/Contract); CDR0000612010; NCCTG-N0723; CALGB-30802; CAN-NCIC-BRC4; N0723 (Other Identifier: CTEP)