Pemetrexed Disodium, Carboplatin, and Radiation Therapy With or Without Cetuximab in Treating Patients With Stage III Non-Small Cell Lung Cancer

A Randomized Phase II Study of Radiation Therapy, Pemetrexed and Carboplatin With or Without Cetuximab in Stage III Non-Small Cell Lung Cancer

RATIONALE: Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also make tumor cells more sensitive to radiation therapy. Giving pemetrexed disodium, carboplatin, and radiation therapy together with cetuximab may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying how well giving pemetrexed disodium and carboplatin together with radiation therapy with or without cetuximab works in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: pemetrexed disodium; Radiation: radiation therapy; Biological: cetuximab

Detailed Description

OBJECTIVES:

Primary

• Determine the overall survival of patients with unresectable stage III non-small cell lung cancer treated with pemetrexed disodium, carboplatin, and thoracic radiotherapy with or without cetuximab.

Secondary

• Determine the failure-free survival and response rates in patients treated with these regimens.
• Correlate epidermal growth factor receptor, erbB2, and K-ras mutations with survival and tumor response in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study.

• Chemoradiotherapy (courses 1-4): Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive pemetrexed disodium IV over 10 minutes followed by carboplatin IV over 30 minutes on days 1, 22, 43, and 64. Patients also undergo thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47.
  • Arm II: Patients receive pemetrexed disodium, carboplatin, and thoracic radiotherapy as in arm I. Patients also receive cetuximab IV over 2 hours on day 1 and then IV over 1 hour on days 8, 15, 22, 29, 36, and 43.
• Consolidation chemotherapy (courses 5-8): Beginning 3-5 weeks after completion of chemoradiotherapy, all patients receive consolidation chemotherapy comprising pemetrexed disodium alone IV over 10 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 3 years.

PROJECTED ACCRUAL: A total of 100 patients (50 per treatment arm) will be accrued for this study within 10-13 months.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Arroyo Grande, California, United States, 93420
      • Arroyo Grande Community Hospital
    • Castro Valley, California, United States, 94546
      • Eden Medical Center
    • Hayward, California, United States, 94545
      • Saint Rose Hospital
    • La Jolla, California, United States, 92093-0658
      • Rebecca and John Moores UCSD Cancer Center
    • Oakland, California, United States, 94609
      • Alta Bates Summit Medical Center - Summit Campus
    • Oakland, California, United States, 94602
      • Highland General Hospital
    • Oakland, California, United States, 94609
      • CCOP - Bay Area Tumor Institute
    • Pleasanton, California, United States, 94588
      • Valley Care Medical Center
    • San Pablo, California, United States, 94806
      • Doctors Medical Center - San Pablo Campus
  • Connecticut
    • Greenwich, Connecticut, United States, 06830
      • Bendheim Cancer Center at Greenwich Hospital
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital
  • Florida
    • Orlando, Florida, United States, 32803-1273
      • Florida Hospital Cancer Institute at Florida Hospital Orlando
  • Georgia
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60640
      • Louis A. Weiss Memorial Hospital
    • La Grange, Illinois, United States, 60525
      • La Grange Memorial Hospital
  • Indiana
    • Fort Wayne, Indiana, United States, 46815
      • Fort Wayne Medical Oncology and Hematology
  • Iowa
    • Bettendorf, Iowa, United States, 52722
      • Hematology Oncology Associates of the Quad Cities
    • Cedar Rapids, Iowa, United States, 52402
      • St. Luke's Hospital
    • Cedar Rapids, Iowa, United States, 52403
      • Mercy Regional Cancer Center at Mercy Medical Center
    • Cedar Rapids, Iowa, United States, 52402
      • Iowa Blood and Cancer Care
    • Iowa City, Iowa, United States, 52242-1002
      • Holden Comprehensive Cancer Center at University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
    • Bel Air, Maryland, United States, 21014
      • Upper Chesapeake Medical Center
    • Elkton MD, Maryland, United States, 21921
      • Union Hospital Cancer Program at Union Hospital
  • Massachusetts
    • Fall River, Massachusetts, United States, 02721
      • Hudner Oncology Center at Saint Anne's Hospital - Fall River
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Saint Luke's Hospital
    • Columbia, Missouri, United States, 65201
      • Missouri Cancer Associates
    • Saint Louis, Missouri, United States, 63141
      • Arch Medical Services, Incorporated at Center for Cancer Care and Research
    • St Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - Saint Louis
    • St. Louis, Missouri, United States, 63131
      • Missouri Baptist Cancer Center
    • St. Louis, Missouri, United States, 63128
      • St. Anthony's Cancer Center
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • Saint Francis Cancer Treatment Center at Saint Francis Memorial Health Center
    • North Platte, Nebraska, United States, 69103
      • Callahan Cancer Center at Great Plains Regional Medical Center
    • Omaha, Nebraska, United States, 68198-6805
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • University Medical Center of Southern Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Nevada Cancer Research Foundation
  • New Hampshire
    • Hooksett, New Hampshire, United States, 03106
      • New Hampshire Oncology - Hematology, PA - Hooksett
    • Laconia, New Hampshire, United States, 03246
      • Lakes Region General Hospital
    • Manchester, New Hampshire, United States, 03103
      • Elliot Regional Cancer Center at Elliot Hospital
  • New Jersey
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New York
    • East Syracuse, New York, United States, 13057
      • CCOP - Hematology-Oncology Associates of Central New York
    • Glens Falls, New York, United States, 12801
      • Charles R. Wood Cancer Center at Glens Falls Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Syracuse, New York, United States, 13210
      • Veterans Affairs Medical Center - Syracuse
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals - Memorial Campus
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital, Incorporated
    • Hendersonville, North Carolina, United States, 28791
      • Pardee Memorial Hospital
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
    • Oklahoma City, Oklahoma, United States, 73120
      • Cancer Care Associates - Mercy Campus
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Miriam Hospital
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Comprehensive Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Roper St. Francis Cancer Center at Roper Hospital
    • Florence, South Carolina, United States, 29501
      • McLeod Regional Medical Center
  • Tennessee
    • Kingsport, Tennessee, United States, 37662
      • Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center
  • Vermont
    • Berlin, Vermont, United States, 05602
      • Mountainview Medical
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care - University Health Center Campus
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Regional Medical Center
    • Martinsville, Virginia, United States, 24115
      • Ravenel Oncology Center at Memorial Hospital of Martinsville and Henry County
    • Norton, Virginia, United States, 24273
      • Southwest Virginia Regional Cancer Center at Wellmonth Health
    • Richmond, Virginia, United States, 23298-0037
      • Virginia Commonwealth University Massey Cancer Center
  • West Virginia
    • Huntington, West Virginia, United States, 25702
      • St. Mary's Regional Cancer Center at St. Mary's Medical 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

1. Histologically or cytologically documented NSCLC, including squamous cell carcinoma, adenocarcinoma including bronchoalveolar cell, and large cell anaplastic carcinoma (including giant and clear cell carcinomas)

2. Eligible Disease Stages: Inoperable IIIA and Selected IIIB - Patients entered must be considered unresectable or inoperable. Patients do not need to have a mediastinoscopy.

   A size of 2 cm or greater by CT is a sufficient criterion for the diagnosis of mediastinal lymph node (N2 or N3) involvement by malignancy. If the largest mediastinal lymph node is less than 2 cm in diameter, a biopsy confirmation of mediastinal nodal involvement is required.

   1. The following patients are eligible:

      • Patients must be M0
      • Patients with any T with N2 or N3 are eligible
      • Patients with T3, N1-N3 disease are eligible if deemed unresectable
      • Patients with T4, any N are eligible provided the T4 status is not determined because of malignant effusion
      • Patients with contralateral mediastinal disease (N3) are eligible if all gross disease can be encompassed in the radiation field in accordance with the homogeneity criteria
      • Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy
      • If a pleural effusion can be seen on the chest CT but not on CXR and is too small to tap, the patient will be eligible. Patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible.

   2. The following patients are NOT eligible:

      • Patients with T3, N0 disease
      • Patients with M1 disease
      • Patients with atelectasis of the entire lung
      • Patients with direct invasion of vertebral body
      • Patients with scalene, supraclavicular, or contralateral hilar node involvement
      • Patients with exudative, bloody, or cytologically malignant effusions
3. Patients must have Measurable Disease: Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥10 mm with spiral CT scan. Lesions that are not considered measurable include bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, abdominal masses that are not confirmed and followed by imaging techniques, cystic lesions and tumor lesions situated in a previously irradiated area.
4. Prior Therapy: ≥ 2 weeks since formal exploratory thoracotomy. No prior chemotherapy for NSCLC, chest radiation therapy or therapy that specifically and directly targets the EGFR pathway
5. ECOG performance status 0-1
6. Positron Emission Tomography (PET) using 18 fluorodeoxyglucose (FDG) must be negative for distant metastasis. PET imaging is mandatory.
7. Weight loss of ≤ 10% in the past 3 months
8. No "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse.
9. Non-pregnant and non-nursing because of significant risk to the fetus/infant
10. Age ≥ 18 years
11. No patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness.
12. No HIV-positive patients receiving combination anti-retroviral therapy because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy
13. No known history of hypersensitivity to carboplatin, pemetrexed or a monoclonal antibody

14. Required Initial Laboratory Values:

    1. Granulocytes ≥ 1,500/mcl
    2. Platelets ≥ 100,000/mcl
    3. Calculated Creatinine Clearance ≥ 45 ml/min
    4. Bilirubin < 1.5 x ULN
    5. AST/ALT < 3 x ULN
    6. Alkaline Phosphatase < 3 x ULN

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: Std Tx + Pemetrexed; Patients receive pemetrexed disodium IV over 10 minutes followed by carboplatin IV over 30 minutes on days 1, 22, 43, and 64. Patients also undergo thoracic radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47.	Drug: carboplatin; AUC = 5 q 21 days for 4 cycles; Drug: pemetrexed disodium; 500 mg/sq m IV q 21 days during chemoradiation and consolidation chemotherapy phases; Radiation: radiation therapy; Thoracic radiotherapy: 70 Gy for 7 weeks beginning on Day 1.
Experimental: Std Tx + Pemetrexed and Cetuximab; Patients receive pemetrexed disodium, carboplatin, and thoracic radiotherapy as in arm I. Patients also receive cetuximab IV over 2 hours on day 1 and then IV over 1 hour on days 8, 15, 22, 29, 36, and 43.	Drug: carboplatin; AUC = 5 q 21 days for 4 cycles; Drug: pemetrexed disodium; 500 mg/sq m IV q 21 days during chemoradiation and consolidation chemotherapy phases; Radiation: radiation therapy; Thoracic radiotherapy: 70 Gy for 7 weeks beginning on Day 1.; Biological: cetuximab; 400 mg/sq m IV over 120 min: Day 1; Week 1 250 mg/sq m IV over 60 min weekly for 6 more weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
18 Month Survival	Percentage of participants who were alive at 18 months. The 18 month survival, with 95% CI, was estimated using the Kaplan-Meier method.	18 months (from randomization)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure-free Survival	Failure-free survival (FFS) is the time from randomization to a failure event, defined as disease progression or death from any cause (which ever occurred first). The median FFS with 95% CI was estimated using the Kaplan-Meier method,	Time from randomization to failure (up to 4 years)
Number of Participants With Overall Tumor Response	Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions;; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions;; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions;; Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs.	Duration of study until progression (up to 4 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival (OS) is defined as the time from patient randomization (arm assignment) to death from any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.	Time from randomization to death (up to 4 years)

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI); Eli Lilly and Company
• Investigators: Study Chair: Ramaswamy Govindan, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Govindan R, Bogart J, Stinchcombe T, Wang X, Hodgson L, Kratzke R, Garst J, Brotherton T, Vokes EE. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011 Aug 10;29(23):3120-5. doi: 10.1200/JCO.2010.33.4979. Epub 2011 Jul 11.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: July 8, 2005
• First Submitted That Met QC Criteria: July 8, 2005
• First Posted (Estimate): July 11, 2005

Study Record Updates

• Last Update Posted (Estimate): October 7, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: stage IIIA non-small cell lung cancer; stage IIIB non-small cell lung cancer; squamous cell lung cancer; large cell lung cancer; adenocarcinoma of the lung; bronchoalveolar cell lung cancer
• 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; Antineoplastic Agents, Immunological; Folic Acid Antagonists; Carboplatin; Pemetrexed; Cetuximab
• Other Study ID Numbers: CALGB 30407; U10CA031946 (U.S. NIH Grant/Contract); CDR0000434616 (Other Identifier: Physician Data Query)