Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer
Condition: Adenosquamous Lung Carcinoma; Bronchioloalveolar Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer
MeSH terms: Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma of Lung; Adenocarcinoma, Bronchiolo-Alveolar
Intervention: Radiation Therapy; Carboplatin; Metformin; Paclitaxel
Intervention description: Radiation therapy (RT) is given in 2 Gy fractions once daily 5 days per week to a total of 30 fractions and 60 Gy. Photons required; 3-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) permitted. Starts within 14 days of randomization (Chemoradiation arm) or 14 days after metformin starts (Chemoradiation + Metformin arm).; 2 AUC (area under the curve) via IV weekly on days 1, 8, 15, 22, 29, and 36 from start of radiation therapy. Two 21 day cycles of 6 AUC via IV starting 28-42 days after the end of radiation therapy.; Metformin is taken orally. Dose escalation begins 2 weeks prior to the initiation of chemoradiation. 500 mg twice daily days 1-7 of metformin. 500 mg three times daily days 8-14 of metformin. Three times a day with the following dosage: 500mg in the morning, 1000mg at noon, and 500mg in the evening concurrent with chemoradiation and through consolidation chemotherapy (days 15-126 of metformin),; 50 mg/m2 via IV weekly on days 1, 8, 15, 22, 29, and 36 from start of radiation therapy. Two 21 day cycles of 200 mg/m2 via IV 28-42 days after the end of radiation therapy.
Intervention MeSH terms: Metformin; Paclitaxel; Carboplatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 170.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well chemotherapy and radiation therapy given with
      or without metformin hydrochloride works in treating patients with stage III non-small cell
      lung cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in
      different ways to stop the growth of tumor cells, either by killing the cells, by stopping
      them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy
      x-rays to kill tumor cells and shrink tumors. Metformin hydrochloride may shrink tumors and
      keep them from coming back. It is not yet known whether chemotherapy and radiation therapy is
      more effective when given with or without metformin hydrochloride in treating stage III
      non-small cell lung cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Pathologically (histologically or cytologically) proven diagnosis of stage IIIA or
             IIIB non-small cell lung cancer within 84 days of registration; eligible histologies
             include adenocarcinoma, adenosquamous, large cell carcinoma, squamous carcinoma,
             non-lobar and non-diffuse bronchoalveolar cell carcinoma or non-small cell lung cancer
             not otherwise specified)

          -  Patients must have measurable disease

          -  Patients must have unresectable disease, be medically inoperable, or unwilling to
             undergo surgical management

          -  Appropriate stage for protocol entry, including no distant metastases, based upon the
             following minimum diagnostic workup:

               -  History/physical examination, including documentation of height, weight, body
                  surface area, and vital signs, within 30 days prior to registration

               -  Computed tomography (CT) with IV contrast or magnetic resonance imaging (MRI)
                  imaging (if CT scan with contrast is medically contraindicated) of the lung and
                  upper abdomen through the adrenal glands, required within 45 days prior to
                  registration (recommended within 30 days prior to registration

               -  MRI of the brain with contrast (or CT with contrast if MRI is medically
                  contraindicated) within 45 days 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 fludeoxyglucose (FDG)-positron emission tomography (PET)/CT required
                  within 45 days prior to registration (recommended within 30 days prior to
                  registration; note: patients do not need to have a separate CT of the chest and
                  upper abdomen with contrast if PET/CT imaging includes a high quality CT with
                  contrast

          -  Zubrod performance status 0-1

          -  Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

          -  Complete blood count(CBC)/differential obtained within 14 days prior to registration
             on study, with adequate bone marrow function defined as follows:

               -  Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

               -  Platelets >= 100,000 cells/mm^3

               -  Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to
                  achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

          -  Adequate renal function within 14 days prior to registration, defined as serum
             creatinine within normal institutional limits or creatinine clearance must be at least
             60 ml/min;

          -  Adequate hepatic function within 14 days prior to registration, defined as total
             bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution and alanine
             aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase ≤
             2.5 x ULN for the institution;

          -  Fasting blood glucose ≤ 125 mg/dL within 14 days prior to registration;

          -  Serum albumin > 3.0 g/dl within 14 days prior to registration;

          -  For women of childbearing potential, a serum pregnancy test within 72 hours prior to
             registration;

          -  Patients with post-obstructive pneumonia are eligible provided they no longer require
             intravenous antibiotics at registration;

          -  Patients must be at least 3 weeks from prior thoracotomy (if performed);

          -  If a pleural effusion is present, the following criteria must be met at registration
             to exclude malignant involvement (incurable M1a 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;

               -  Effusions that are minimal (i.e. not visible under ultrasound guidance) and that
                  are too small to safely tap are eligible.

          -  Women of childbearing potential and male participants must practice adequate
             contraception throughout the study;

        Exclusion Criteria:

          -  Patients with mixed small cell and non-small cell histologies

          -  Patients with distant metastasis

          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
             for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity,
             or cervix are all permissible)

          -  Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
             different cancer is allowable

          -  Prior radiotherapy to the region of the study cancer that would result in overlap of
             radiation therapy fields

          -  Patients currently using metformin (metformin hydrochloride), other oral hypoglycemic
             agents or insulin

          -  Patients with any history of allergic reaction to paclitaxel or other taxanes or
             carboplatin

          -  Patients with a history of chronic kidney disease or lactic acidosis

          -  Patients with >= 10% weight loss within the past month

          -  Severe, active co-morbidity, defined as follows:

               -  Diagnosis of type I or type II diabetes mellitus

               -  Uncontrolled neuropathy >= grade 2 regardless of cause

               -  Unstable angina and/or congestive heart failure requiring hospitalization within
                  the last 6 months

               -  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 of
                  registration

               -  Severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic
                  disease

               -  Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4
                  count < 200 cells/microliter; note that patients who are HIV positive are
                  eligible, provided they are under treatment with highly active antiretroviral
                  therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior
                  to registration; note also that HIV testing is not required for eligibility for
                  this protocol

               -  End-stage renal disease (ie, on dialysis or dialysis has been recommended)

          -  Pregnancy or women of childbearing potential and men who are sexually active and not
             willing/able to use medically acceptable forms of contraception