High-Dose or Standard-Dose Radiation Therapy and Chemotherapy With or Without Cetuximab in Treating Patients With Newly Diagnosed Stage III Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery
Condition: Lung Cancer; Radiation Toxicity
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Cetuximab; Carboplatin; Paclitaxel; 60 Gy RT; 74 Gy RT
Intervention description: Loading dose: 400 mg/m2, IV, one week prior to start of radiation therapy (RT). Then, beginning day 1 of RT, 250 mg/m2, IV, weekly; for 60 Gy arm for 15 weeks, for 74 Gy arm for 16 weeks.; Concurrent: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy; for 74 Gy arms, on day 43 as well.
Consolidation, 3 weeks after completion of RT, AUC=6, IV, days 1 and 22.; Concurrent: 45 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy (RT); for 74 Gy arms, on day 43 as well.
Consolidation, 3 weeks after completion of RT, 200 mg/m2, IV, days 1 and 22.; Radiation therapy (RT) in once-daily, 2 Gy fractions, given in 30 fractions over the course of 6 weeks.; Radiation therapy (RT) in once-daily, 2 Gy fractions, given in 37 fractions over the course of 7.5 weeks.
Intervention MeSH terms: Paclitaxel; Carboplatin; Cetuximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This study was revised 06/18/08 to a 2x2 factorial design to evaluate the addition of cetuximab to the radiation therapy regimens.
Masking: None (Open Label)
Enrollment: 544.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: radiation toxicity; stage IIIA non-small cell lung cancer; stage IIIB non-small cell lung cancer

Summary:

      RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in
      chemotherapy, such as paclitaxel, carboplatin work in different ways to stop the growth of
      tumor cells, either by killing the cells or by stopping them from dividing. 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. It is not yet known whether high-dose radiation
      therapy is more effective than standard-dose radiation therapy when given together with
      combination chemotherapy with or without cetuximab in treating patients with non-small cell
      lung cancer.

      PURPOSE: This randomized phase III trial is studying high-dose or standard-dose radiation
      therapy given together with chemotherapy with or without cetuximab to see how well they work
      in treating patients with newly diagnosed stage III non-small cell lung cancer that cannot be
      removed by surgery.
    

Eligibility criteria:

        Inclusion criteria:

          1. Pathologically proven (either histologic or cytologic) diagnosis of Stage IIIA or IIIB
             non-small cell lung cancer (NSCLC); excluding patients with N3 disease based on
             supraclavicular or contralateral hilar adenopathy, [according to American Joint
             Committee on Cancer (AJCC) Staging, 6th edition; see appendix III] within 12 weeks of
             registration; patients who present with N2 or N3 disease and an undetectable NSCLC
             primary tumor also are eligible.

          2. Patients must be considered unresectable or inoperable; Note: Patients who have had a
             nodal recurrence after surgery for an early-stage NSCLC are eligible if the following
             criteria are met:

               -  Nodal recurrence must be N1 or N2; N3 is not eligible.

               -  The initial primary must have been staged as T1-2, N0, M0.

               -  The node must be biopsied within 12 weeks of registration.

               -  The node must be measurable.

               -  The patient must not have received prior chemotherapy or radiation for this lung
                  cancer.

               -  Prior curative surgery must have been at least 6 months prior to the nodal
                  recurrence.

               -  The exception to a prior invasive malignancy does not apply to the initial lung
                  primary.

          3. Stage III A or B disease, including no distant metastases, based upon the following
             minimum diagnostic workup are acceptable:

               -  History/physical examination, including documentation of height, weight, body
                  surface area (BSA), and vital signs within 8 weeks prior to registration;

               -  Computed tomographic (CT)/Magnetic Resonance Imaging (MRI) imaging of the lung
                  and upper abdomen through the adrenal glands within 6 weeks prior to
                  registration;

               -  An MRI of the brain with contrast (or CT with contrast if MRI is medically
                  contraindicated) within 6 weeks prior to registration; Note: The use of
                  intravenous contrast is required for the MRI or CT. An MRI without contrast is
                  only permitted if the patient has a contrast allergy.

               -  Whole-body fluorodeoxyglucose (FDG) - Positron Emission Tomography(PET) or PET/CT
                  or if no PET is available, a bone scan is required within 6 weeks prior to
                  registration; Note: If a PET is done that shows clear adrenals and lungs, then a
                  CT scan of chest only is permitted.

          4. If a pleural effusion is present, the following criteria must be met to exclude
             malignant involvement (incurable T4 disease):

               -  When pleural fluid is visible on both the CT scan and on a chest x-ray, a
                  pleuracentesis is required to confirm that the pleural fluid is cytologically
                  negative.

               -  Exudative pleural effusions are excluded, regardless of cytology;

               -  Effusions that are minimal (i.e. not visible on chest x-ray) that are too small
                  to safely tap are eligible.

          5. Patients must have measurable or evaluable disease.

          6. Patients with post-obstructive pneumonia are eligible.

          7. Patients must be at least 3 weeks from prior thoracotomy (if performed).

          8. Zubrod Performance Status 0-1;

          9. Age ≥ 18;

         10. Pulmonary function tests (PFTs) including forced expiratory volume in one second
             (FEV1) within 12 weeks prior to registration; for FEV1, the best value obtained pre-
             or post bronchodilator must be ≥ 1.2 liters/second or ≥ 50% predicted.

         11. Complete blood count (CBC)/differential obtained within 2 weeks prior to registration
             on study, with adequate bone marrow function defined as follows:

               -  Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;

               -  Platelets ≥ 100,000 cells/mm3;

               -  Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to
                  achieve Hgb ≥ 10.0 g/dl is acceptable.)

         12. Serum creatinine within normal institutional limits or creatinine clearance ≥60
             ml/min;

         13. Bilirubin must be within or below normal institutional limits;

         14. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2.5 x the
             institutional upper limit of normal (IULN);

         15. Patient must sign study specific informed consent prior to study entry.

        Exclusion Criteria:

          1. N3 supraclavicular disease;

          2. Greater than minimal, exudative, or cytologically positive pleural effusions;

          3. Involved contralateral hilar nodes (i.e. greater than 1.5 cm on short axis or positive
             on PET scan);

          4. ≥ 10% weight loss within the past month;

          5. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
             for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the
             breast, oral cavity, or cervix are all permissible.

          6. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
             different cancer is allowable.

          7. Prior radiotherapy to the region of the study cancer that would result in overlap of
             radiation therapy fields;

          8. Prior therapy that specifically and directly targets the epidermal growth factor
             receptor (EGFR) pathway;

          9. Prior severe infusion reaction to a monoclonal antibody;

         10. Severe, active co-morbidity, defined as follows:

               -  Significant history of uncontrolled cardiac disease; i.e., uncontrolled
                  hypertension, unstable angina, myocardial infarction within the last 6 months,
                  uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection
                  fraction.

               -  Transmural myocardial infarction within the last 6 months;

               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time
                  of registration;

               -  Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
                  requiring hospitalization or precluding study therapy within 30 days before
                  registration;

               -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;

               -  Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease
                  Control and Prevention (CDC) definition; note, however, that human
                  immunodeficiency virus (HIV) testing is not required for entry into this
                  protocol. The need to exclude patients with AIDS from this protocol is necessary
                  because the treatments involved in this protocol may be significantly
                  immunosuppressive. Protocol-specific requirements may also exclude
                  immuno-compromised patients.

         11. Pregnancy or women of childbearing potential and men who are sexually active and not
             willing/able to use medically acceptable forms of contraception; this exclusion is
             necessary because the treatment involved in this study may be significantly
             teratogenic.

         12. Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin;

         13. Uncontrolled neuropathy grade 2 or greater regardless of cause.